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Sample records for progressive castration-resistant prostate

  1. Tpl2 induces castration resistant prostate cancer progression and metastasis.

    PubMed

    Lee, Hye Won; Cho, Hyun Jung; Lee, Se Jeong; Song, Hye Jin; Cho, Hee Jin; Park, Min Chul; Seol, Ho Jun; Lee, Jung-Il; Kim, Sunghoon; Lee, Hyun Moo; Choi, Han Yong; Nam, Do-Hyun; Joo, Kyeung Min

    2015-05-01

    Progression to metastatic castration resistant prostate cancer (CRPC) is the major lethal pathway of prostate cancer (PC). Herein, we demonstrated that tumor progression locus 2 (Tpl2) kinase is the fundamental molecule provoking progression and metastasis of CRPC. Tpl2 upregulates CXCR4 and focal adhesion kinase (FAK) to activate CXCL12/CXCR4 and FAK/Akt signalling pathway. Consequently, epithelial-mesenchymal transition (EMT) and stemness of androgen depletion independent (ADI) PC cells are induced, which is dependent on the kinase activity of Tpl2. In vitro, proliferation, clonogenicity, migration, invasion and chemoresistance of ADI PC cells were enhanced by Tpl2. In vivo, Tpl2 overexpression and downregulation showed significant stimulatory and inhibitory effects on tumorigenic and metastatic potential of ADI PC cells, respectively. Moreover, the prognostic effects of Tpl2 and expressional correlation between Tpl2 and EMT-related molecules/CXCR4 were validated in clinical PC databases. Since Tpl2 exerts metastatic progression promoting activities in CRPC, Tpl2 could serve as a novel therapeutic target for metastatic CRPC. PMID:25274482

  2. Progress in the mechanism and drug development of castration-resistant prostate cancer.

    PubMed

    Zuo, Minzan; Xu, Xi; Li, Tinghan; Ge, Raoling; Li, Zhiyu

    2016-05-01

    Although prostate cancer can initially respond to androgen deprivation therapy, it will inevitably relapse and switch to a castration-resistant state. The progress in understanding the mechanism of castration-resistant prostate cancer (CRPC) has led to the evolution of novel agents, including sipuleucel-T as an immunomodulant agent, enzalutamide as an androgen receptor antagonist, docetaxel as a chemotherapeutic agent and radium-223 as a radiopharmaceutical agent. In this review, we discuss the main mechanisms of CRPC and the development of promising agents along with the novel therapies in the clinic. New therapeutic challenges remain, such as the identification of predictive biomarkers and the optimal combinations of agents. Future investigation is still needed for a better understanding of CRPC. PMID:27149562

  3. The hallmarks of castration-resistant prostate cancers.

    PubMed

    Katsogiannou, Maria; Ziouziou, Hajer; Karaki, Sara; Andrieu, Claudia; Henry de Villeneuve, Marie; Rocchi, Palma

    2015-07-01

    Prostate cancer has become a real public health issue in industrialized countries, mainly due to patients' relapse by castration-refractory disease after androgen ablation. Castration-resistant prostate cancer is an incurable and highly aggressive terminal stage of prostate cancer, seriously jeopardizing the patient's quality of life and lifespan. The management of castration-resistant prostate cancer is complex and has opened new fields of research during the last decade leading to an improved understanding of the biology of the disease and the development of new therapies. Most advanced tumors resistant to therapy still maintain the androgen receptor-pathway, which plays a central role for survival and growth of most castration-resistant prostate cancers. Many mechanisms induce the emergence of the castration resistant phenotype through this pathway. However some non-related AR pathways like neuroendocrine cells or overexpression of anti-apoptotic proteins like Hsp27 are described to be involved in CRPC progression. More recently, loss of expression of tumor suppressor gene, post-transcriptional modification using miRNA, epigenetic alterations, alternatif splicing and gene fusion became also hallmarks of castration-resistant prostate cancer. This review presents an up-to-date overview of the androgen receptor-related mechanisms as well as the latest evidence of the non-AR-related mechanisms underlying castration-resistant prostate cancer progression. PMID:25981454

  4. Variant allele of HSD3B1 increases progression to castration-resistant prostate cancer

    PubMed Central

    Nastiuk, Kent L.; Li, Jinliang; Gu, Jun; Wu, Ming; Zhang, Qimin; Lin, Hanqing; Wu, Denglong

    2016-01-01

    BACKGROUND 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1), which is a rate-limiting enzyme that catalyzes the conversion of adrenal-derived steroid dehydroepiandrosterone to DHT, may be a promising target for treating castration-resistant prostate cancer (CRPC). METHODS From 2004 to 2011, a total of 103 consecutive patients presenting with advanced prostate cancer were included in this study. All patients were treated with surgical castration as androgen deprivation therapy (ADT). Germline DNA was extracted from archived tissue from each patient and sequenced. PSA half-time (representing rate to PSA nadir after ADT), the incidence of, and time to CRPC occurrence, and cause-specific mortality rates were determined during the 3-10 year follow-up. The perioperative data and postoperative outcomes are compared. The patients were retrospectively analyzed for survival time. RESULTS Of the 103 patient samples analyzed, 18 harbored a heterozygous variant (1245C) HSD3B1 gene, while 85 patients were homozygous wild-type (1245A) for HSD3B1. The two groups were homogenous for age, PSA, Gleason and metastases rate preoperatively. The incidence of CRPC observed in the variant group was significantly higher than that of wild-type group (100% vs 64.7%, respectively; p = 0.003). Despite this higher incidence of CRPC, there were no significant differences in time to develop CRPC, or in cause-specific mortality. Further, neither PSA half-time, nor time to biochemical recurrence (rising PSA is only one of the defining characteristics of CRPC) were different between the variant and wild-type groups. CONCLUSION Prostate cancer patients who harbored the heterozygous variant HSD3B1 (1245C) are more likely to develop to CRPC, but do not have shorter time to biochemical recurrence, shorter survival time or higher mortality risk. PMID:25731771

  5. Disease Progression/Clinical Outcome Model for Castration-Resistant Prostate Cancer in Patients Treated With Eribulin

    PubMed Central

    van Hasselt, JGC; Gupta, A; Hussein, Z; Beijnen, JH; Schellens, JHM; Huitema, ADR

    2015-01-01

    Frameworks that associate cancer dynamic disease progression models with parametric survival models for clinical outcome have recently been proposed to support decision making in early clinical development. Here we developed such a disease progression clinical outcome model for castration-resistant prostate cancer (CRPC) using historical phase II data of the anticancer agent eribulin. Disease progression was captured using the dynamics of prostate-specific antigen (PSA). For clinical outcome, overall survival (OS) was used. The model for PSA dynamics comprised parameters for baseline PSA (23.2 ng/ml, relative standard error (RSE) 16.5%), growth rate (0.00879 day−1, RSE 12.6%), drug effect (0.241 µg·h·l−1 day−1, RSE 32.6%), and resistance development (0.0113 day−1, RSE 44.3%). OS was modeled according to a Weibull distribution. Predictors for survival included model-predicted PSA time to nadir (TTN), PSA growth rate, Eastern Cooperative Oncology Group (ECOG) score, and baseline PSA. The developed framework can be considered to support informative design and analysis of drugs developed for CRPC. PMID:26312162

  6. Tumour responses following a steroid switch from prednisone to dexamethasone in castration-resistant prostate cancer patients progressing on abiraterone

    PubMed Central

    Lorente, D; Omlin, A; Ferraldeschi, R; Pezaro, C; Perez, R; Mateo, J; Altavilla, A; Zafeirou, Z; Tunariu, N; Parker, C; Dearnaley, D; Gillessen, S; de Bono, J; Attard, G

    2014-01-01

    Background: Abiraterone is a CYP17A1 inhibitor that improves survival in castration-resistant prostate cancer (CRPC). Abiraterone is licensed in combination with prednisone 5 mg twice daily to prevent a syndrome of secondary mineralocorticoid excess. We hypothesised that a ‘steroid switch' from prednisone to dexamethasone would induce secondary responses in patients progressing on abiraterone and prednisone 5 mg b.i.d. Methods: We performed a ‘steroid switch' in patients with CRPC at PSA progression on abiraterone and prednisolone. Patients were monitored for secondary declines in PSA, radiological tumour regression and toxicity. Results: A retrospective analysis of 30 CRPC patients who underwent a steroid switch from prednisolone to dexamethasone while on abiraterone was performed. A total of six patients (20%) had a ⩾50% PSA decline that was confirmed by a second PSA level at least 3 weeks later. In all, 11 patients (39.2%) had a confirmed ⩾30% PSA decline. Median time to PSA progression on abiraterone and dexamethasone was 11.7 weeks (95% CI: 8.6–14.8 weeks) in the whole cohort and 27.6 weeks (95% CI: 14.5–40.7 weeks) in patients who achieved a confirmed 50% PSA decline. Nine patients had RECIST evaluable disease: two of these patients had RECIST partial response, six patients had stable disease and one patient had progressive disease at the first imaging assessment. Treatment was well tolerated, with no grade 3 and grade 4 adverse events. One patient had to be reverted to prednisolone because of grade 2 hypotension. Conclusions: Durable PSA responses occur in up to 40% of patients following a ‘steroid switch' for PSA progression on abiraterone and prednisone. Studies are ongoing to elucidate the mechanisms underlying this response. PMID:25314055

  7. Synergistic targeting of PI3K/AKT pathway and androgen receptor axis significantly delays castration-resistant prostate cancer progression in vivo.

    PubMed

    Thomas, Christian; Lamoureux, Francois; Crafter, Claire; Davies, Barry R; Beraldi, Eliana; Fazli, Ladan; Kim, Soojin; Thaper, Daksh; Gleave, Martin E; Zoubeidi, Amina

    2013-11-01

    The progression to castration-resistant prostate cancer (CRPC) correlates with gain-of-function of the androgen receptor (AR) and activation of AKT. However, as single agents, AR or AKT inhibitors result in a reciprocal feedback loop. Therefore, we hypothesized that combination of an AKT inhibitor with an antiandrogen might result in a more profound, long-lasting remission of CRPC. Here, we report that the AKT inhibitor AZD5363 potently inhibits proliferation and induces apoptosis in prostate cancer cell lines expressing the AR and has anticancer activity in vivo in androgen-sensitive and castration-resistant phases of the LNCaP xenograft model. However, we found that the effect of castration-resistant tumor growth inhibition and prostate-specific antigen (PSA) stabilization is transient and resistance occurs with increasing PSA after approximately 30 days of treatment. Mechanistically, we found that single agent AZD5363 induces increase of AR binding to androgen response element, AR transcriptional activity, and AR-dependent genes such as PSA and NKX3.1 expression. These effects were overcome by the combination of AZD5363 with the antiandrogen bicalutamide, resulting in synergistic inhibition of cell proliferation and induction of apoptosis in vitro, and prolongation of tumor growth inhibition and PSA stabilization in CRPC in vivo. This study provides a preclinical proof-of-concept that combination of an AKT inhibitor with antiandrogen results in prolonged disease stabilization in a model of CRPC. PMID:23966621

  8. Progression of metastatic castrate-resistant prostate cancer: impact of therapeutic intervention in the post-docetaxel space

    PubMed Central

    2011-01-01

    Despite the proven success of hormonal therapy for prostate cancer using chemical or surgical castration, most patients eventually will progress to a phase of the disease that is metastatic and shows resistance to further hormonal manipulation. This has been termed metastatic castrate-resistant prostate cancer (mCRPC). Despite this designation, however, there is evidence that androgen receptor (AR)-mediated signaling and gene expression can persist in mCRPC, even in the face of castrate levels of androgen. This may be due in part to the upregulation of enzymes involved in androgen synthesis, the overexpression of AR, or the emergence of mutant ARs with promiscuous recognition of various steroidal ligands. The therapeutic options were limited and palliative in nature until trials in 2004 demonstrated that docetaxel chemotherapy could significantly improve survival. These results established first-line docetaxel as the standard of care for mCRPC. After resistance to further docetaxel therapy develops, treatment options were once again limited. Recently reported results from phase 3 trials have shown that additional therapy with the novel taxane cabazitaxel (with prednisone), or treatment with the antiandrogen abiraterone (with prednisone) could improve survival for patients with mCRPC following docetaxel therapy. Compared with mitoxantrone/prednisone, cabazitaxel/prednisone significantly improved overall survival, with a 30% reduction in rate of death, in patients with progression of mCRPC after docetaxel therapy in the TROPIC trial. Similarly, abiraterone acetate (an inhibitor of androgen biosynthesis) plus prednisone significantly decreased the rate of death by 35% compared with placebo plus prednisone in mCRPC patients progressing after prior docetaxel therapy in the COU-AA-301 trial. Results of these trials have thus established two additional treatment options for mCRPC patients in the "post-docetaxel space." In view of the continued AR-mediated signaling on m

  9. Therapeutic vaccines and immunotherapy in castration-resistant prostate cancer: current progress and clinical applications.

    PubMed

    Gulley, James L; Madan, Ravi A; Heery, Christopher R

    2013-01-01

    Results of recent clinical trials have intensified interest in immunotherapy for cancer. Among the most promising candidates for immunotherapy are patients with prostate cancer. Results of therapeutic vaccine clinical trials in this population have suggested statistically significant and clinically meaningful improvements in overall survival, with substantially fewer side effects than with chemotherapy. Of particular interest are sipuleucel-T, the first U.S. Food and Drug Administration-approved therapeutic cancer vaccine, and PSA-TRICOM (PROSTVAC), a therapeutic cancer vaccine in phase III testing. The immune checkpoint inhibitor ipilimumab is also stirring considerable interest, with two phase III trials ongoing in prostate cancer. This article highlights data emerging from these trials and addresses remaining questions and practical clinical implications of this therapeutic strategy. PMID:23714490

  10. [Current status of castration-resistant prostate cancer translational research].

    PubMed

    Maeno, Atsushi; Habuchi, Tomonori

    2016-01-01

    Recently, new drugs including abiraterone and enzalutamide have been able to be used for castration resistant prostate cancer(CRPC) patients. However, a subset of these patients who receive the new drugs does not response to the therapies. Furthermore, most patients who initially response to the drugs, progress to secondary resistance eventually. Therefore, it is important to investigate a novel therapeutic target and a novel treatment-selection marker for CRPC. In this review, we focused on AR-V7, TMPRSS2-ERG fusion gene and EP4 antagonist as representative translational researches. PMID:26793877

  11. Targeting molecular resistance in castration-resistant prostate cancer.

    PubMed

    Chandrasekar, Thenappan; Yang, Joy C; Gao, Allen C; Evans, Christopher P

    2015-01-01

    Multiple mechanisms of resistance contribute to the inevitable progression of hormone-sensitive prostate cancer to castration-resistant prostate cancer (CRPC). Currently approved therapies for CRPC include systemic chemotherapy (docetaxel and cabazitaxel) and agents targeting the resistance pathways leading to CRPC, including enzalutamide and abiraterone. While there is significant survival benefit, primary and secondary resistance to these therapies develops rapidly. Up to one-third of patients have primary resistance to enzalutamide and abiraterone; the remaining patients eventually progress on treatment. Understanding the mechanisms of resistance resulting in progression as well as identifying new targetable pathways remains the focus of current prostate cancer research. We review current knowledge of mechanisms of resistance to the currently approved treatments, development of adjunctive therapies, and identification of new pathways being targeted for therapeutic purposes. PMID:26329698

  12. Mechanisms of resistance in castration-resistant prostate cancer (CRPC).

    PubMed

    Chandrasekar, Thenappan; Yang, Joy C; Gao, Allen C; Evans, Christopher P

    2015-06-01

    Despite advances in prostate cancer diagnosis and management, morbidity from prostate cancer remains high. Approximately 20% of men present with advanced or metastatic disease, while 29,000 men continue to die of prostate cancer each year. Androgen deprivation therapy (ADT) has been the standard of care for initial management of advanced or metastatic prostate cancer since Huggins and Hodges first introduced the concept of androgen-dependence in 1972, but progression to castration-resistant prostate cancer (CRPC) occurs within 2-3 years of initiation of ADT. CRPC, previously defined as hormone-refractory prostate cancer, is now understood to still be androgen dependent. Multiple mechanisms of resistance help contribute to the progression to castration resistant disease, and the androgen receptor (AR) remains an important driver in this progression. These mechanisms include AR amplification and hypersensitivity, AR mutations leading to promiscuity, mutations in coactivators/corepressors, androgen-independent AR activation, and intratumoral and alternative androgen production. More recently, identification of AR variants (ARVs) has been established as another mechanism of progression to CRPC. Docetaxel chemotherapy has historically been the first-line treatment for CRPC, but in recent years, newer agents have been introduced that target some of these mechanisms of resistance, thereby providing additional survival benefit. These include AR signaling inhibitors such as enzalutamide (Xtandi, ENZA, MDV-3100) and CYP17A1 inhibitors such as abiraterone acetate (Zytiga). Ultimately, these agents will also fail to suppress CRPC. While some of the mechanisms by which these agents fail are unique, many share similarities to the mechanisms contributing to CRPC progression. Understanding these mechanisms of resistance to ADT and currently approved CRPC treatments will help guide future research into targeted therapies. PMID:26814148

  13. Mechanisms of resistance in castration-resistant prostate cancer (CRPC)

    PubMed Central

    Chandrasekar, Thenappan; Yang, Joy C.; Gao, Allen C.

    2015-01-01

    Despite advances in prostate cancer diagnosis and management, morbidity from prostate cancer remains high. Approximately 20% of men present with advanced or metastatic disease, while 29,000 men continue to die of prostate cancer each year. Androgen deprivation therapy (ADT) has been the standard of care for initial management of advanced or metastatic prostate cancer since Huggins and Hodges first introduced the concept of androgen-dependence in 1972, but progression to castration-resistant prostate cancer (CRPC) occurs within 2-3 years of initiation of ADT. CRPC, previously defined as hormone-refractory prostate cancer, is now understood to still be androgen dependent. Multiple mechanisms of resistance help contribute to the progression to castration resistant disease, and the androgen receptor (AR) remains an important driver in this progression. These mechanisms include AR amplification and hypersensitivity, AR mutations leading to promiscuity, mutations in coactivators/corepressors, androgen-independent AR activation, and intratumoral and alternative androgen production. More recently, identification of AR variants (ARVs) has been established as another mechanism of progression to CRPC. Docetaxel chemotherapy has historically been the first-line treatment for CRPC, but in recent years, newer agents have been introduced that target some of these mechanisms of resistance, thereby providing additional survival benefit. These include AR signaling inhibitors such as enzalutamide (Xtandi, ENZA, MDV-3100) and CYP17A1 inhibitors such as abiraterone acetate (Zytiga). Ultimately, these agents will also fail to suppress CRPC. While some of the mechanisms by which these agents fail are unique, many share similarities to the mechanisms contributing to CRPC progression. Understanding these mechanisms of resistance to ADT and currently approved CRPC treatments will help guide future research into targeted therapies. PMID:26814148

  14. Enzalutamide for patients with metastatic castration-resistant prostate cancer

    PubMed Central

    Ramadan, Wijdan H; Kabbara, Wissam K; Al Basiouni Al Masri, Hiba S

    2015-01-01

    Objective To review and evaluate current literature on the US Food and Drug Administration (FDA)-approved drug enzalutamide (XTANDI®) in metastatic castration-resistant prostate cancer. Data sources Literature search was done through PubMed using the terms enzalutamide, MDV3100, abiraterone, and castration-resistant prostate cancer. Data from FDA product labels were also used. Study selection and data extraction Recent and relevant studies were included in the review. Collected clinical trials were screened and evaluated. Data synthesis Enzalutamide is an androgen receptor (AR) inhibitor with high selectivity and affinity to the AR. It was approved by the FDA to treat metastatic castration-resistant prostate cancer in patients previously treated with docetaxel, after a Phase III trial (AFFIRM) that showed a 4.8-month survival benefit in this population. Recently, the FDA expanded the approval of enzalutamide as first-line therapy for metastatic castration-resistant prostate cancer (mCRPC) who did not receive chemotherapy. Moreover, enzalutamide is shown to be associated with an acceptable safety profile. Conclusion Enzalutamide has been shown to be both safe and effective in improving overall survival in metastatic castration-resistant prostate cancer postchemotherapy with docetaxel and as a first line treatment before initiation of chemotherapy. However, additional studies and head-to-head trials are needed. PMID:25945058

  15. [Pathophysiology and therapy of castration-resistant prostate cancer].

    PubMed

    Merseburger, A S; Kuczyk, M A; Wolff, J M

    2013-02-01

    Advanced prostate cancer that progresses under androgen deprivation therapy has long been thought to be refractory to further hormonal treatment. The identification of the mechanism of cancer cells has revolutionized this understanding. Today it is known that castration-resistant prostate cancer (CRPC) still receives signals through the androgen receptor transduction pathways and furthermore is sensitive to hormone therapy. New substances, such as abiraterone, enzalutamide (MDV3100) and TAK 700 target these mechanisms of resistance of cancer cells, stop testosterone production and show not only better tolerance but also effective antitumor activity. Due to the heterogeneity of tumors with cells in varying states of differentiation, the treatment of CRPC with androgen deprivation therapy remains a cornerstone of disease management. To what extent the experimental findings and the recommendations in the guidelines are put into practice was the subject of a survey among urologists analyzing their treatment strategies with CRPC patients. PMID:23160609

  16. Chemotherapy-based treatment for castration-resistant prostate cancer.

    PubMed

    Seruga, Bostjan; Tannock, Ian F

    2011-09-20

    Most men with metastatic prostate cancer respond to various types of androgen ablation but progress to castration-resistant disease. The TAX 327 and Southwest Oncology Group (SWOG) 99-16 clinical trials established docetaxel-based chemotherapy as preferred first-line treatment for most men with symptomatic metastatic castration-resistant prostate cancer (mCRPC). However, only about half receive benefit from docetaxel, and those who respond initially progress and eventually die of (or with) mCRPC. Both cellular mechanisms and the tumor microenvironment are implicated in the development of resistance to docetaxel. New agents are being evaluated for men with mCRPC, either as first-line treatment in combination with docetaxel, or in men progressing during or after treatment with docetaxel. Thus far, agents evaluated in phase III trials in combination with docetaxel have not improved outcome, including the vaccine GVAX, high-dose vitamin D (DN-101), and the antiangiogenic agent bevacizumab. In contrast, cabazitaxel, a taxane that is not cross-resistant to docetaxel, substantially improved the outcome of men progressing during or after treatment with docetaxel-based chemotherapy when compared with mitoxantrone and prednisone. However, translation of benefit of cabazitaxel demonstrated in the TROPIC (Treatment of Hormone-Refractory Metastatic Prostate Cancer) trial into general oncologic practice will be challenging because this agent may cause serious toxicity. With the approval of less toxic hormonal agents (eg, abiraterone acetate) in the setting of docetaxel-resistant mCRPC, clinicians will have an opportunity to balance benefits and harms of new agents in an individual patient and may be able to use different agents in sequence. PMID:21844499

  17. Management of castrate-resistant prostate cancer in older men.

    PubMed

    Ged, Yasser; Horgan, Anne M

    2016-03-01

    Prostate cancer is the most common cancer diagnosed in men with the highest incidence in older men. Older men are more likely to present with metastatic disease compared with younger patients and eventually all will develop castrate resistant disease. In recent years, a number of new treatment options have demonstrated survival benefits for metastatic castrate resistant prostate cancer. However, the lack of randomized trials directly comparing the different available options results in some uncertainty on how best to choose and sequence therapy. In this paper, we outline the therapeutic options available to men with metastatic castrate-resistant prostate cancer, including cytotoxic therapy, hormonal agents and bone-directed therapy. We focus particularly on the evidence for specific treatment options and the challenges faced in choosing the appropriate therapy for the older patient. PMID:26907565

  18. New developments in the treatment of castration resistant prostate cancer

    PubMed Central

    Wadia, Roxanne; Petrylak, Daniel P

    2014-01-01

    In the past 5 years, the treatment and understanding of metastatic castrate resistant prostate cancer (CRPC) have improved dramatically. Our understanding of the mechanisms of castration resistance has allowed for the development of new drugs to target prostate cancer, and our understanding of genetic mutations may give us new tools with which to more accurately diagnose and be able to predict the course of this heterogeneous disease. This article summarizes the recent advances in the understanding of the development of CRPC, as well as the new drugs and targets, which have evolved from this basic research. PMID:24759588

  19. Current Treatment Strategies for Castration-Resistant Prostate Cancer

    PubMed Central

    Kim, Sun Il

    2011-01-01

    Prostate cancer is the most common cancer in men in United States and the fifth most common cancer in men in Korea. Although the majority of patients with metastatic prostate cancer initially respond to androgen deprivation therapy, almost all patients will eventually progress to develop castration-resistant prostate cancer (CRPC). Treatment options for CRPC remain limited. Prostate cancer was considered unresponsive to chemotherapy until the mid-1990s, when mitoxantrone combined with prednisone was shown to play a role in the palliative treatment of patients with CRPC. In 2004, two large randomized clinical trials demonstrated for the first time a small but significant survival advantage of docetaxel-based chemotherapy compared with mitoxantrone in patients with metastatic CRPC. Recently, cabazitaxel was shown to improve survival in patients with metastatic CRPC who progressed after docetaxel-based chemotherapy. Sipuleucel-T was also demonstrated to improve overall survival in patients with asymptomatic or minimally symptomatic metastatic CRPC. Along with mitoxantrone and docetaxel, cabazitaxel and sipuleucel-T are now approved for use in metastatic CRPC by the US Food and Drug Administration. There have been multiple early-phase clinical trials of various agents for the treatment of CRPC, and some are in phase III development. This review focuses on the key clinical trials of various treatment options of CRPC currently in use and under investigation. PMID:21461278

  20. The mutational landscape of lethal castration-resistant prostate cancer.

    PubMed

    Grasso, Catherine S; Wu, Yi-Mi; Robinson, Dan R; Cao, Xuhong; Dhanasekaran, Saravana M; Khan, Amjad P; Quist, Michael J; Jing, Xiaojun; Lonigro, Robert J; Brenner, J Chad; Asangani, Irfan A; Ateeq, Bushra; Chun, Sang Y; Siddiqui, Javed; Sam, Lee; Anstett, Matt; Mehra, Rohit; Prensner, John R; Palanisamy, Nallasivam; Ryslik, Gregory A; Vandin, Fabio; Raphael, Benjamin J; Kunju, Lakshmi P; Rhodes, Daniel R; Pienta, Kenneth J; Chinnaiyan, Arul M; Tomlins, Scott A

    2012-07-12

    Characterization of the prostate cancer transcriptome and genome has identified chromosomal rearrangements and copy number gains and losses, including ETS gene family fusions, PTEN loss and androgen receptor (AR) amplification, which drive prostate cancer development and progression to lethal, metastatic castration-resistant prostate cancer (CRPC). However, less is known about the role of mutations. Here we sequenced the exomes of 50 lethal, heavily pre-treated metastatic CRPCs obtained at rapid autopsy (including three different foci from the same patient) and 11 treatment-naive, high-grade localized prostate cancers. We identified low overall mutation rates even in heavily treated CRPCs (2.00 per megabase) and confirmed the monoclonal origin of lethal CRPC. Integrating exome copy number analysis identified disruptions of CHD1 that define a subtype of ETS gene family fusion-negative prostate cancer. Similarly, we demonstrate that ETS2, which is deleted in approximately one-third of CRPCs (commonly through TMPRSS2:ERG fusions), is also deregulated through mutation. Furthermore, we identified recurrent mutations in multiple chromatin- and histone-modifying genes, including MLL2 (mutated in 8.6% of prostate cancers), and demonstrate interaction of the MLL complex with the AR, which is required for AR-mediated signalling. We also identified novel recurrent mutations in the AR collaborating factor FOXA1, which is mutated in 5 of 147 (3.4%) prostate cancers (both untreated localized prostate cancer and CRPC), and showed that mutated FOXA1 represses androgen signalling and increases tumour growth. Proteins that physically interact with the AR, such as the ERG gene fusion product, FOXA1, MLL2, UTX (also known as KDM6A) and ASXL1 were found to be mutated in CRPC. In summary, we describe the mutational landscape of a heavily treated metastatic cancer, identify novel mechanisms of AR signalling deregulated in prostate cancer, and prioritize candidates for future study. PMID

  1. Stilbenes inhibit androgen receptor expression in 22Rv1 castrate-resistant prostate cancer cells

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Androgen receptor (AR) signaling plays an important role in the development and progression of prostate cancer (PCa). Importantly, AR continues to be expressed in advanced stages of castrate-resistant PCa (CRPC), where it can have ligand- independent activity. Identification of naturally occurring s...

  2. Targeting Bone Metastases in Metastatic Castration-Resistant Prostate Cancer.

    PubMed

    El-Amm, Joelle; Aragon-Ching, Jeanny B

    2016-01-01

    Skeletal involvement in metastatic castrate-resistant prostate cancer (mCRPC) is common and results in significant morbidity and mortality. The interaction of prostate cancer with the bone microenvironment contributes to progression of cancer in the bone leading to skeletal-related events (SREs). Studies aimed at targeting the bone have been carried out over the recent years. Bisphosphonates are synthetic pyrophosphate analogs first investigated for their role in SRE prevention with zoledronic acid as the main bisphosphonate that is approved by the US Food and Drug Administration for retardation of skeletal events in men with metastatic prostate cancer. Denosumab is another bone-targeted agent against uncontrolled osteolysis and serves as a RANK ligand inhibitor, superior to zoledronic acid in delaying SREs. Radiopharmaceuticals have played a role in targeting the bone microenvironment mainly in pain palliation in mCRPC utilizing strontium or samarium in the remote past, but only radium-223 is the first radiopharmaceutical that has yielded improvement in overall survival. The combination and sequencing strategies of these agents is the subject of multiple ongoing trials to guide the best use of these emerging agents. PMID:27042152

  3. Targeting Bone Metastases in Metastatic Castration-Resistant Prostate Cancer

    PubMed Central

    El-Amm, Joelle; Aragon-Ching, Jeanny B.

    2016-01-01

    Skeletal involvement in metastatic castrate-resistant prostate cancer (mCRPC) is common and results in significant morbidity and mortality. The interaction of prostate cancer with the bone microenvironment contributes to progression of cancer in the bone leading to skeletal-related events (SREs). Studies aimed at targeting the bone have been carried out over the recent years. Bisphosphonates are synthetic pyrophosphate analogs first investigated for their role in SRE prevention with zoledronic acid as the main bisphosphonate that is approved by the US Food and Drug Administration for retardation of skeletal events in men with metastatic prostate cancer. Denosumab is another bone-targeted agent against uncontrolled osteolysis and serves as a RANK ligand inhibitor, superior to zoledronic acid in delaying SREs. Radiopharmaceuticals have played a role in targeting the bone microenvironment mainly in pain palliation in mCRPC utilizing strontium or samarium in the remote past, but only radium-223 is the first radiopharmaceutical that has yielded improvement in overall survival. The combination and sequencing strategies of these agents is the subject of multiple ongoing trials to guide the best use of these emerging agents. PMID:27042152

  4. Integrated Simulation Framework for Toxicity, Dose Intensity, Disease Progression, and Cost Effectiveness for Castration-Resistant Prostate Cancer Treatment With Eribulin

    PubMed Central

    van Hasselt, JGC; Gupta, A; Hussein, Z; Beijnen, JH; Schellens, JHM; Huitema, ADR

    2015-01-01

    Quantitative model-based analyses are helpful to support decision-making in drug development. In oncology, disease progression/clinical outcome (DPCO) models have been used for early predictions of clinical outcome, but most of such approaches did not include adverse events or dose intensity. In addition, cost-effectiveness evaluations of investigational compounds are becoming increasingly important. Here, we developed an integrated model-based framework including relevant treatment effects for patients with castration-resistant prostate cancer treated with the anticancer agent eribulin. The framework included (i) a DPCO model relating prostate-specific antigen (PSA) dynamics to survival; (ii) models for adverse events including dose-limiting neutropenia and other graded toxicities; (iii) a model for Eastern Cooperative Oncology Group (ECOG) performance score; (iv) a model for dropout; (v) the consideration of cost effectiveness. The model allowed simulation of realistic treatment courses. Subsequently, simulations evaluating alternative treatment protocols or patient characteristics were performed in order to derive inferences on expected efficacy and cost effectiveness. PMID:26312161

  5. Continuous versus intermittent docetaxel for metastatic castration resistant prostate cancer.

    PubMed

    Gyawali, Bishal; Koomulli-Parambil, Sahadudheen; Iddawela, Mahesh

    2016-06-01

    Docetaxel (DTX) is a standard chemotherapeutic agent for metastatic castration resistant prostate cancer (mCRPC). However, given a number of toxicities associated with DTX, considerable debate exists regarding the optimal number of DTX cycles to be administered in this setting. In clinic, it is a usual practice to continue DTX until toxicities or disease progression precludes its administration. Therefore, we undertook a comprehensive review of the literature on intermittent versus continuous chemotherapy administration in this setting. Although there is no head-to-head comparison of these two approaches, our review discovered many studies which show that intermittent approach is a very feasible and attractive option with lower toxicities and better quality of life. Because of the availability of many newer agents that can be used post-docetaxel, stopping DTX early seems to be more appropriate with introduction of docetaxel or newer agents upon progression. This review summarizes the data from available studies regarding the feasibility and controversies of intermittent docetaxel in prostate cancer. PMID:27157868

  6. Androgen biosynthesis in castration-resistant prostate cancer

    PubMed Central

    Penning, Trevor M

    2014-01-01

    Prostate cancer is the second leading cause of death in adult males in the USA. Recent advances have revealed that the fatal form of this cancer, known as castration-resistant prostate cancer (CRPC), remains hormonally driven despite castrate levels of circulating androgens. CRPC arises as the tumor undergoes adaptation to low levels of androgens by either synthesizing its own androgens (intratumoral androgens) or altering the androgen receptor (AR). This article reviews the major routes to testosterone and dihydrotestosterone synthesis in CRPC cells and examines the enzyme targets and progress in the development of isoform-specific inhibitors that could block intratumoral androgen biosynthesis. Because redundancy exists in these pathways, it is likely that inhibition of a single pathway will lead to upregulation of another so that drug resistance would be anticipated. Drugs that target multiple pathways or bifunctional agents that block intratumoral androgen biosynthesis and antagonize the AR offer the most promise. Optimal use of enzyme inhibitors or AR antagonists to ensure maximal benefits to CRPC patients will also require application of precision molecular medicine to determine whether a tumor in a particular patient will be responsive to these treatments either alone or in combination. PMID:24829267

  7. Divergent clonal evolution of castration resistant neuroendocrine prostate cancer

    PubMed Central

    Beltran, Himisha; Prandi, Davide; Mosquera, Juan Miguel; Benelli, Matteo; Puca, Loredana; Cyrta, Joanna; Marotz, Clarisse; Giannopoulou, Eugenia; Chakravarthi, Balabhadrapatruni V.S.K.; Varambally, Sooryanarayana; Tomlins, Scott A.; Nanus, David M.; Tagawa, Scott T.; Van Allen, Eliezer M.; Elemento, Olivier; Sboner, Andrea; Garraway, Levi A.; Rubin, Mark A.; Demichelis, Francesca

    2016-01-01

    An increasingly recognized resistance mechanism to androgen receptor (AR)-directed therapy in prostate cancer involves epithelial plasticity, wherein tumor cells demonstrate low to absent AR expression and often neuroendocrine features. The etiology and molecular basis for these “alternative” treatment-resistant cell states remain incompletely understood. Here, by analyzing whole exome sequencing data of metastatic biopsies from patients, we observed significant genomic overlap between castration resistant adenocarcinoma (CRPC-Adeno) and neuroendocrine histologies (CRPC-NE); analysis of serial progression samples points to a model most consistent with divergent clonal evolution. Genome-wide DNA methylation revealed marked epigenetic differences between CRPC-NE and CRPC-Adeno that also designated cases of CRPC-Adeno with clinical features of AR-independence as CRPC-NE, suggesting that epigenetic modifiers may play a role in the induction and/or maintenance of this treatment-resistant state. This study supports the emergence of an alternative, “AR-indifferent” cell state through divergent clonal evolution as a mechanism of treatment resistance in advanced prostate cancer. PMID:26855148

  8. Molecular processes leading to aberrant androgen receptor signaling and castration resistance in prostate cancer

    PubMed Central

    Hu, Rong; Denmeade, Samuel R; Luo, Jun

    2011-01-01

    Hormone therapies targeting androgen receptor signaling are the mainstay of treatment for patients with advanced prostate cancer. The length of clinical remission induced by hormone therapies varies substantially among treated patients. Why some patients progress rapidly after treatment while others benefit with prolonged remission is a question that remains unsolved. The androgen receptor signaling pathway is the key molecular determinant of castration resistance, and a key target for prostate cancer drug design. Recent advances in characterizing molecular processes leading to the development of castration-resistant prostate cancer, including the discovery of multiple androgen receptor splicing variants, offer opportunities for rational development of new clinical tools or approaches to predict, monitor or control/prevent prostate cancer progression in the castrate setting. PMID:21318111

  9. Gene Expression Profiling Analysis of Castration-Resistant Prostate Cancer

    PubMed Central

    Wang, Xuelei; Wen, Jiling; Li, Rongbing; Qiu, Guangming; Zhou, Lan; Wen, Xiaofei

    2015-01-01

    Background Prostate cancer is a global health issue. Usually, men with metastatic disease will progress to castration-resistant prostate cancer (CRPC). We aimed to identify the differentially expressed genes (DEGs) in tumor samples from non-castrated and castrated men from LNCaP Orthotopic xenograft models of prostate cancer and to study the mechanisms of CRPC. Material/Methods In this work, GSE46218 containing 4 samples from non-castrated men and 4 samples from castrated men was downloaded from Gene Expression Omnibus. We identified DEGs using limma Geoquery in R, the Robust Multi-array Average (RMA) method in Bioconductor, and Bias methods, followed by constructing an integrated regulatory network involving DEGs, miRNAs, and TFs using Cytoscape. Then, we analyzed network motifs of the integrated gene regulatory network using FANMOD. We selected regulatory modules corresponding to network motifs from the integrated regulatory network by Perl script. We preformed gene ontology (GO) and pathway enrichment analysis of DEGs in the regulatory modules using DAVID. Results We identified total 443 DEGs. We built an integrated regulatory network, found three motifs (motif 1, motif 2 and motif 3), and got two function modules (module 1 corresponded to motif 1, and module 2 corresponded to motif 2). Several GO terms (such as regulation of cell proliferation, positive regulation of macromolecule metabolic process, phosphorylation, and phosphorus metabolic process) and two pathways (pathway in cancer and Melanoma) were enriched. Furthermore, some significant DEGs (such as CAV1, LYN, FGFR3 and FGFR3) were related to CPRC development. Conclusions These genes might play important roles in the development and progression of CRPC. PMID:25592164

  10. A profile of enzalutamide for the treatment of advanced castration resistant prostate cancer

    PubMed Central

    Greasley, Rosa; Khabazhaitajer, Mohammad; Rosario, Derek J

    2015-01-01

    Recent advances in understanding the mechanisms underlying the development and progression of castration resistant prostate cancer from androgen-sensitive prostate cancer have provided new avenues exploring efficacious therapies in a disease which is the second leading cause of cancer deaths among men in the western world. In the evolution of second generation anti-androgens, enzalutamide, a novel androgen-receptor signaling inhibitor, has emerged targeting multiple steps within the androgenic stimulation pathway. This review discusses what is currently known of the mechanisms surrounding castration resistant prostate cancer development and the current human clinical trials to determine whether enzalutamide presents a new hope for men with advanced prostate cancer. The issues of therapy resistance, withdrawal effects and cross-resistance are briefly touched upon. PMID:26109877

  11. Progression-free and overall survival in metastatic castration-resistant prostate cancer treated with abiraterone acetate can be predicted with serial C11-acetate PET/CT

    PubMed Central

    Farnebo, Jacob; Wadelius, Agnes; Sandström, Per; Nilsson, Sten; Jacobsson, Hans; Blomqvist, Lennart; Ullén, Anders

    2016-01-01

    Abstract In this retrospective study, we evaluated the benefit of repeated carbon 11 (C11)-acetate positron emission tomography/computed tomography (PET/CT) to assess response in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA). A total of 30 patients with mCRPC were monitored with C11-acetate PET/CT and PSA levels during their treatment with AA. Retrospective evaluation of their response was made after 102 days (median; range 70–155) of treatment. Statistical analyses were employed to detect predictors of progression-free survival (PFS) and overall survival (OS), and potential correlation between serum levels of PSA, standardized uptake values (SUVpeak), and bone lesion index measured from PET were investigated. At follow-up 10 patients exhibited partial response (PR), 10 progressive disease (PD), and 10 stable disease (SD), as assessed by PET/CT. In survival analysis, both PR and PD were significantly associated with PFS and OS. CT response was also associated with OS, but only 19/30 patients demonstrated a lesion meeting target lesion criteria according to RECIST 1.1. No PET/CT baseline characteristic was significantly associated with PFS or OS. A PSA response (reduction in the level by >50%) could also predict PFS and OS. In the subgroup lacking a PSA response, those with PD had significantly shorter OS than those with PR or SD. PFS and OS in patients with mCRPC treated with AA can be predicted from repeated C11-acetate PET/CT. This may be of particular clinical value in patients who do not exhibit a PSA response to treatment. PMID:27495034

  12. Radiographic Progression-Free Survival As a Response Biomarker in Metastatic Castration-Resistant Prostate Cancer: COU-AA-302 Results

    PubMed Central

    Morris, Michael J.; Molina, Arturo; Small, Eric J.; de Bono, Johann S.; Logothetis, Christopher J.; Fizazi, Karim; de Souza, Paul; Kantoff, Philip W.; Higano, Celestia S.; Li, Jinhui; Kheoh, Thian; Larson, Steven M.; Matheny, Shannon L.; Naini, Vahid; Burzykowski, Tomasz; Griffin, Thomas W.; Scher, Howard I.; Ryan, Charles J.

    2015-01-01

    Purpose Progression-free survival (PFS) in metastatic castration-resistant prostate cancer (mCRPC) trials has been inconsistently defined and poorly associated with overall survival (OS). A reproducible quantitative definition of radiographic PFS (rPFS) was tested for association with a coprimary end point of OS in a randomized trial of abiraterone in patients with mCRPC. Patients and Methods rPFS was defined as ≥ two new lesions on an 8-week bone scan plus two additional lesions on a confirmatory scan, ≥ two new confirmed lesions on any scan ≥ 12 weeks after random assignment, and/or progression in nodes or viscera on cross-sectional imaging, or death. rPFS was assessed by independent review at 15% of deaths and by investigator review at 15% and 40% of deaths. rPFS and OS association was evaluated by Spearman's correlation. Results A total of 1,088 patients were randomly assigned to abiraterone plus prednisone or prednisone alone. At first interim analysis, the hazard ratio (HR) by independent review was 0.43 (95% CI, 0.35 to 0.52; P < .001; abiraterone plus prednisone: median rPFS, not estimable; prednisone: median rPFS, 8.3 months). Similar HRs were obtained by investigator review at the first two interim analyses (HR, 0.49; 95% CI, 0.41 to 0.60; P < .001 and HR, 0.53; 95% CI, 0.45 to 0.62; P < .001, respectively), validating the imaging data assay used. Spearman's correlation coefficient between rPFS and OS was 0.72. Conclusion rPFS was highly consistent and highly associated with OS, providing initial prospective evidence on further developing rPFS as an intermediate end point in mCRPC trials. PMID:25624432

  13. Tolerability of cabazitaxel in patients with metastatic castration-resistant prostate cancer progressing after docetaxel and abiraterone acetate: a single-institution experience.

    PubMed

    Francini, Edoardo; Fiaschi, Anna I; Petrioli, Roberto; Laera, Letizia; Bianco, Vincenzo; Ponchietti, Roberto; Roviello, Giandomenico

    2015-09-01

    Both abiraterone acetate (AA) and cabazitaxel (Cbz) have been shown to prolong survival in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing during or after docetaxel (D). Although no standard sequencing has been established as yet, Cbz has recently been proven to be active after AA. However, to date, few data are available on its safety in this setting. Therefore, the primary endpoint of this study was to investigate Cbz tolerability in mCRPC patients treated previously with D and AA. From April 2011 to the present, 43 mCRPC patients received AA after D at our institution. Of these, 22 patients were subsequently treated with Cbz and were evaluable for toxicity in the present retrospective study. Cbz was administered at a dose of 25 mg/m plus 10 mg oral prednisone every 3 weeks. Adverse events (AEs) were reported using the NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 3.0. Despite the advanced stage of disease and frailty of our study population, there were no unexpected side effects. The most common AEs were hematologic. Neutropenia was observed in nine (40.9%) patients and of grade≥3 in six (27.2%). No febrile neutropenia occurred. The most common nonhematologic AEs were diarrhea and asthenia, reported in eight (36.3%) and in five (22.7%) patients, respectively. In this setting, Cbz toxicity seems to be manageable and comparable with second-line Cbz. Therefore, our results seem to support the safety of Cbz as a third-line treatment for mCRPC patients. PMID:26053281

  14. Developing imaging strategies for castration resistant prostate cancer

    PubMed Central

    Fox, Josef J.; Morris, Michael J.; Larson, Steven M.; Schöder, Heiko; Scher, Howard I.

    2012-01-01

    Recent advances in the understanding of castrate-resistant prostate cancer (CRPC) have lead to a growing number of experimental therapies, many of which are directed against the androgen-receptor (AR) signaling axis. These advances generate the need for reliable molecular imaging biomarkers to non-invasively determine efficacy, and to better guide treatment selection of these promising AR-targeted drugs. Methods We draw on our own experience, supplemented by review of the current literature, to discuss the systematic development of imaging biomarkers for use in the context of CRPC, with a focus on bone scintigraphy, F-18 fluorodeoxyglucose (FDG)-positron emission tomography (PET) and PET imaging of the AR signaling axis. Results The roadmap to biomarker development mandates rigorous standardization and analytic validation of an assay before it can be qualified successfully for use in an appropriate clinical context. The Prostate Cancer Working Group 2 (PCWG2) criteria for “radiographic” progression by bone scintigraphy serve as a paradigm of this process. Implemented by the Prostate Cancer Clinical Trials Consortium (PCCTC), these consensus criteria may ultimately enable the co-development of more potent and versatile molecular imaging biomarkers. Purported to be superior to single-photon bone scanning, the added value of Na18F-PET for imaging of bone metastases is still uncertain. FDG-PET already plays an integral role in the management of many diseases, but requires further evaluation before being qualified in the context of CRPC. PET tracers that probe the AR signaling axis, such as 18F-FDHT and 89Zr-591, are now under development as pharmacodynamic markers, and as markers of efficacy, in tandem with FDG-PET. Semi-automated analysis programs for facilitating PET interpretation may serve as a valuable tool to help navigate the biomarker roadmap. Conclusions Molecular imaging strategies, particularly those that probe the AR signaling axis, have the potential

  15. Management of metastatic castration-resistant prostate cancer.

    PubMed

    Antonarakis, Emmanuel S

    2011-01-01

    The management of men with metastatic castration-resistant prostate cancer (CRPC) has taken several leaps forward in the last 2 years, with the demonstration of improved overall survival with three novel agents (sipuleucel-T, cabazitaxel, and abiraterone acetate), and a significant delay in skeletal-related events observed with denosumab. The pipeline of systemic therapies in prostate cancer remains strong, as multiple agents with a diverse array of mechanisms of action are demonstrating preliminary signs of clinical benefit, leading to more definitive phase III confirmatory trials. In this review, we will discuss the evolving landscape of treatment options for men with CRPC, with a particular focus on currently approved and emerging treatment options for these patients. Knowledge of these evolving standards will help to optimize delivery of care and long term outcomes in men with advanced CRPC. PMID:23789039

  16. Metastatic castration-resistant prostate cancer: changing landscape with cabazitaxel.

    PubMed

    Fernández, Ovidio; Afonso, Javier; Vázquez, Sergio; Campos, Begoña; Lázaro, Matín; León, Luis; Antón Aparicio, Luis M

    2014-03-01

    Docetaxel is the standard first-line chemotherapy for men with metastatic castration-resistant prostate cancer. Until recently, there was no standard therapy after failure of docetaxel treatment. Cabazitaxel has been shown to improve overall survival in this setting. As a result, the treatment paradigm for mCRPC is changing rapidly. The improved survival shown with cabazitaxel provides an important new opportunity to treat men with mCRPC after docetaxel treatment. Despite the toxicity recorded in the pivotal study, subsequent trials have shown that cabazitaxel is a safe drug. Patient selection and the optimal interval between prior docetaxel treatment and cabazitaxel remain the critical issues. According to a subanalysis of the various studies discussed in this review, there is a patient profile that will probably benefit from use of cabazitaxel after docetaxel failure. Cabazitaxel represents a new treatment option for patients with prostate cancer. PMID:24217332

  17. Integrative Molecular Profiling Reveals Asparagine Synthetase Is a Target in Castration-Resistant Prostate Cancer

    PubMed Central

    Sircar, Kanishka; Huang, Heng; Hu, Limei; Cogdell, David; Dhillon, Jasreman; Tzelepi, Vassiliki; Efstathiou, Eleni; Koumakpayi, Ismaël H.; Saad, Fred; Luo, Dijun; Bismar, Tarek A.; Aparicio, Ana; Troncoso, Patricia; Navone, Nora; Zhang, Wei

    2013-01-01

    The identification of new and effective therapeutic targets for the lethal, castration-resistant stage of prostate cancer (CRPC) has been challenging because of both the paucity of adequate frozen tissues and a lack of integrated molecular analysis. Therefore, in this study, we performed a genome-wide analysis of DNA copy number alterations from 34 unique surgical CRPC specimens and 5 xenografts, with matched transcriptomic profiling of 25 specimens. An integrated analysis of these data revealed that the asparagine synthetase (ASNS) gene showed a gain in copy number and was overexpressed at the transcript level. The overexpression of ASNS was validated by analyzing other public CRPC data sets. ASNS protein expression, as detected by reverse-phase protein lysate array, was tightly correlated with gene copy number. In addition, ASNS protein expression, as determined by IHC analysis, was associated with progression to a therapy-resistant disease state in TMAs that included 77 castration-resistant and 40 untreated prostate cancer patient samples. Knockdown of ASNS by small-interfering RNAs in asparagine-deprived media led to growth inhibition in both androgen-responsive (ie, LNCaP) and castration-resistant (ie, C4-2B) prostate cancer cell lines and in cells isolated from a CRPC xenograft (ie, MDA PCa 180-30). Together, our results suggest that ASNS is up-regulated in cases of CRPC and that depletion of asparagine using ASNS inhibitors will be a novel strategy for targeting CRPC cells. PMID:22245216

  18. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer.

    PubMed

    Beltran, Himisha; Prandi, Davide; Mosquera, Juan Miguel; Benelli, Matteo; Puca, Loredana; Cyrta, Joanna; Marotz, Clarisse; Giannopoulou, Eugenia; Chakravarthi, Balabhadrapatruni V S K; Varambally, Sooryanarayana; Tomlins, Scott A; Nanus, David M; Tagawa, Scott T; Van Allen, Eliezer M; Elemento, Olivier; Sboner, Andrea; Garraway, Levi A; Rubin, Mark A; Demichelis, Francesca

    2016-03-01

    An increasingly recognized resistance mechanism to androgen receptor (AR)-directed therapy in prostate cancer involves epithelial plasticity, in which tumor cells demonstrate low to absent AR expression and often have neuroendocrine features. The etiology and molecular basis for this 'alternative' treatment-resistant cell state remain incompletely understood. Here, by analyzing whole-exome sequencing data of metastatic biopsies from patients, we observed substantial genomic overlap between castration-resistant tumors that were histologically characterized as prostate adenocarcinomas (CRPC-Adeno) and neuroendocrine prostate cancer (CRPC-NE); analysis of biopsy samples from the same individuals over time points to a model most consistent with divergent clonal evolution. Genome-wide DNA methylation analysis revealed marked epigenetic differences between CRPC-NE tumors and CRPC-Adeno, and also designated samples of CRPC-Adeno with clinical features of AR independence as CRPC-NE, suggesting that epigenetic modifiers may play a role in the induction and/or maintenance of this treatment-resistant state. This study supports the emergence of an alternative, 'AR-indifferent' cell state through divergent clonal evolution as a mechanism of treatment resistance in advanced prostate cancer. PMID:26855148

  19. ASC-J9(®) suppresses castration resistant prostate cancer progression via degrading the enzalutamide-induced androgen receptor mutant AR-F876L.

    PubMed

    Wang, Ronghao; Lin, Wanying; Lin, Changyi; Li, Lei; Sun, Yin; Chang, Chawnshang

    2016-08-28

    Androgen deprivation therapy (ADT) with the newly developed powerful anti-androgen enzalutamide (Enz, also known as MDV3100) has promising therapeutic effects to suppress castration resistant prostate cancer (CRPC) and extending patients' lives an extra 4.8 months. However, most Enz therapy eventually fails with the development of Enz resistance. The detailed mechanisms how CRPC develops Enz resistance remain unclear and may involve multiple mechanisms. Among them, the induction of the androgen receptor (AR) mutant AR-F876L in some CRPC patients may represent one driving force that confers Enz resistance. Here, we demonstrate that the AR degradation enhancer, ASC-J9(®), not only degrades wild-type AR, but also has the ability to target AR-F876L. The consequence of suppressing AR-F876L may then abrogate AR-F876L mediated CRPC cell proliferation and metastasis. Thus, developing ASC-J9(®) as a new therapeutic approach may represent a novel therapy to better suppress CRPC that has already developed Enz resistance. PMID:27233475

  20. Update on options for treatment of metastatic castration-resistant prostate cancer

    PubMed Central

    Vishnu, Prakash; Tan, Winston W

    2010-01-01

    Background: Prostate cancer is one of the most common cancers in men in US and European countries. Despite having a favorable prognosis, the incidence of incurable metastatic disease and mortality in the US is about 28,000 per year. Although hormone-based androgen deprivation therapies typically result in rapid responses, nearly all patients eventually develop progressive castration-resistant disease state. With readily available prostate-specific antigen (PSA) testing, most of these patients are asymptomatic and manifest progression simply as a rising PSA. In patients with castration-resistant prostate cancer (CRPC), the median survival is about 1–2 years, with improvements in survival seen mostly with docetaxel-based regimens. The purpose of this article is to review the recent developments in the treatment of advanced CRPC. Recent findings: Since the two landmark trials (TAX-327 and Southwest Oncology Group 99–16) in CRPC, several newer cytotoxic drugs (epothilones, satraplatin), targeted agents (abiraterone, MDV3100) and vaccines have been tested in phase II and III setting with promising results. Conclusions: The role of newer agents in the treatment of CRPC still needs to be validated by phase III trials, which are currently ongoing. Whilst the novel biomarkers, ‘circulating tumor cells’, have been shown to provide important prognostic information and are anticipated to be incorporated in future clinical decision-making, their exact utility and relevance calls for a larger prospective validation. PMID:20616956

  1. Castration-resistant prostate cancer: new science and therapeutic prospects

    PubMed Central

    Bellmunt, Joaquim; Oh, William K.

    2010-01-01

    There is a growing number of new therapies targeting different pathways that will revolutionize patient management strategies in castration-resistant prostate cancer (CRPC) patients. Today there are more clinical trial options for CRPC treatment than ever before, and there are many promising agents in late-stage clinical testing. The hypothesis that CRPC frequently remains driven by a ligand-activated androgen receptor (AR) and that CRPC tissues exhibit substantial residual androgen levels despite gonadotropin-releasing hormone therapy, has led to the evaluation of new oral compounds such as abiraterone and MDV 3100. Their results, coupled with promising recent findings in immunotherapy (eg sipuleucel-T) and with agents targeting angiogenesis (while awaiting the final results of the CALGB trial 90401) will most probably impact the management of patients with CRPC in the near future. Other new promising agents need further development. With our increased understanding of the biology of this disease, further trial design should incorporate improved patient selection so that patient populations are those who may be most likely to benefit from treatment. PMID:21789134

  2. [Treatment of metastatic castration-resistant prostate cancer].

    PubMed

    Caffo, Orazio

    2015-01-01

    The treatment of metastatic castration-resistant prostate cancer (mCRPC) represents one of the oncological fields where the most impressive improvements has been observed in the last decades. At the beginning of this century, the expected survival of mCRPC patients was not more than 12 months. After the introduction of docetaxel in the clinical practice in 2004, and the recent availability of new drugs cabazitaxel, abiraterone acetate, enzalutamide, and radium-223 the landscape is dramatically changed with an expected median survival of about three years. The possibility of administering docetaxel, abiraterone acetate, and enzalutamide as first line treatment, and cabazitaxel, abiretone acetate, and enzalutamide as second line, as well as the availability of radium-223 for the treatment of mCRPC patients regardless of chemotherapy administration, changed the natural history of the disease. At the same time, it is probable that also the biology of the disease is changing with the appearance of mechanisms of resistance which are common to all the drugs. This plays a central role in sequencing the available drugs not only in the first and second line setting but also beyond the second line. The future challenges for the oncologists will be to develop new drugs able to overcome the resistances, mainly when they are native, to find the optimal sequence to optimize the use of available drugs, to place at the best place other active drugs, such as vaccines and radiopharmaceuticals, to exploit the new drugs also in a hormone-sensitive phase. PMID:25621779

  3. Denosumab as a promising novel bone-targeted agent in castration resistant prostate cancer.

    PubMed

    Dellis, Athanasios; Papatsoris, Athanasios G

    2014-01-01

    Fortunately, more therapeutic progress has been achieved during the last 3 years for patients with castration resistant prostate cancer (CRPC) than during the previous 30 years. During this limited time frame, six compounds (sipuleucel-T, cabazitaxel, denosumab, abiraterone, radium-223 and enzalutamide, listed in chronologic order) yielded positive results in Phase III trials (Fizazi K. Nonhormone therapy for metastatic castration-resistant prostate cancer. Soc Clin Oncol Educ Book 2013;2013:161-5; Papatsoris AG, Karamouzis MV, Papavassiliou AG. Novel biological agents for the treatment of hormone-refractory prostate cancer (HRPC). Curr Med Chem 2005;12(3):277-96). Regarding skeletal related event (SREs) in patients with CRPC the last 20 years bisphosphonates (i.e., zolendronic acid) were the standard of care until the development of denosumab, which is a novel receptor-activated nuclear factor kappa-β ligand inhibitor. Recent studies demonstrated that denosumab (subcutaneous use) was better than zolendronic acid (intravenous use) for the prevention of SREs and the increase of the bone-metastasis-free survival, while the rate and grade of adverse effects was similar, except for osteonecrosis of the jaw and hypocalcemia. Cost-effectiveness of denosumab is under review in ongoing comparative studies. PMID:24074253

  4. Phase II Trial of Capecitabine and Weekly Docetaxel for Metastatic Castrate Resistant Prostate Cancer

    PubMed Central

    Vaishampayan, Ulka N.; Marur, Shanthi; Heilbrun, Lance K.; Cher, Michael L.; Dickow, Brenda; Smith, Daryn W.; Al Hasan, Samir A.; Eliason, James

    2013-01-01

    Purpose Synergy is observed with the combination of capecitabine and docetaxel due to docetaxel mediated up-regulation of thymidine phosphorylase. A phase II trial was performed with the combination for metastatic, castrate resistant prostate cancer. Materials and Methods Eligible patients had metastatic, castrate resistant prostate cancer, no prior chemotherapy for metastatic disease and normal organ function. Docetaxel (36 mg/m2 per week intravenously) on days 1, 8 and 15, and capecitabine (1,250 mg/m2 per day in 2 divided doses) on days 5 to 18 were administered in 28-day cycles. The response was assessed every 2 cycles. Biomarker correlative studies were performed on blood dihydropyrimidine dehydrogenase, and the thymidine phosphorylase-to-dihydropyrimidine dehydrogenase and thymidine synthase-to-dihydropyrimidine dehydrogenase ratios in available prostate tumor tissue. Results A total of 30 patients with a median age of 69 years were enrolled in the study. We noted bone pain in 21 patients (70%), Gleason score 8 or higher in 18 (60%), measurable disease progression in 9, bone scan progression in 18 and prostate specific antigen progression in 22. Grade 3 or 4 neutropenia was seen in 3 patients and grade 3 hand-foot syndrome was found in 2. No treatment related deaths occurred. A prostate specific antigen response of 50% or greater decrease was observed in 22 patients (73%), of whom 9 (30%) had 90% or greater decrease. A partial response was noted in 5 of 9 patients (56%) with measurable disease. Median time to progression was 6.7 months (90% CI 4.2–7.7) and median overall survival was 22.0 months (90% CI 18.4–25.3). Conclusions The combination was well tolerated and it demonstrated favorable response rates with durable remission and survival outcomes. PMID:19447430

  5. Serum follicle-stimulating hormone levels predict time to development of castration-resistant prostate cancer

    PubMed Central

    Hoare, Dylan; Skinner, Thomas A.A.; Black, Angela; Robert Siemens, D.

    2015-01-01

    Introduction: Treatment of advancing prostate cancer focuses on blocking the activation of the androgen receptor with resultant prolonged perturbation of the hypothalamic-pituitary-gonadal axis. Androgen deprivation therapy (ADT) is marked, however, by eventual progression to castration- resistant prostate cancer (CRPC). Emerging evidence has postulated that follicle-stimulating hormone (FSH) may lead to proliferative and mutagenic responses of prostate cancer. We investigated the association of serum FSH and time to castration resistance. Methods: This was a single-centre retrospective study assessing serum FSH levels of patients undergoing ADT for advancing prostate cancer. The primary outcome was time of ADT initiation to the development of CRPC. For each patient on treatment and with castrate levels of testosterone, the maximum FSH value between ADT commencement and CRPC was identified and recorded. FSH was analyzed as a continuous and categorical variable. Cox multivariate regression in a step-wise fashion was used to explore the association between FSH levels and time to CRPC. Results: From a database of 323 prostate cancer patients actively managed with ADT, 103 men had a documented FSH value while castrate, with 45 men progressing to CRPC. The mean ± standard deviation maximum FSH value of these patients was 6.66 ± 4.22 mIU/mL (range: 1.5–28.1). The mean duration from ADT commencement to CRPC was 3.03 ± 0.34 years (range: 0.36–9.71). Univariate analysis suggested a trend of a negative correlation between FSH values and time to castrate resistance. A FSH value of less than or equal to the lowest tertile (4.8 mIU/mL) was associated with a longer time to CRPC (hazard ratio 0.46; p = 0.006). In the Cox regression analysis, elevated FSH was associated with a shorter duration time to CRPC (p = 0.03). Conclusions: This retrospective, single-centre study would suggest there may be an association between serum FSH levels and time to CRPC for men treated

  6. Sox2 Is an Androgen Receptor-Repressed Gene That Promotes Castration-Resistant Prostate Cancer

    PubMed Central

    Kregel, Steven; Kiriluk, Kyle J.; Rosen, Alex M.; Cai, Yi; Reyes, Edwin E.; Otto, Kristen B.; Tom, Westin; Paner, Gladell P.; Szmulewitz, Russell Z.; Vander Griend, Donald J.

    2013-01-01

    Despite advances in detection and therapy, castration-resistant prostate cancer continues to be a major clinical problem. The aberrant activity of stem cell pathways, and their regulation by the Androgen Receptor (AR), has the potential to provide insight into novel mechanisms and pathways to prevent and treat advanced, castrate-resistant prostate cancers. To this end, we investigated the role of the embryonic stem cell regulator Sox2 [SRY (sex determining region Y)-box 2] in normal and malignant prostate epithelial cells. In the normal prostate, Sox2 is expressed in a portion of basal epithelial cells. Prostate tumors were either Sox2-positive or Sox2-negative, with the percentage of Sox2-positive tumors increasing with Gleason Score and metastases. In the castration-resistant prostate cancer cell line CWR-R1, endogenous expression of Sox2 was repressed by AR signaling, and AR chromatin-IP shows that AR binds the enhancer element within the Sox2 promoter. Likewise, in normal prostate epithelial cells and human embryonic stem cells, increased AR signaling also decreases Sox2 expression. Resistance to the anti-androgen MDV3100 results in a marked increase in Sox2 expression within three prostate cancer cell lines, and in the castration-sensitive LAPC-4 prostate cancer cell line ectopic expression of Sox2 was sufficient to promote castration-resistant tumor formation. Loss of Sox2 expression in the castration-resistant CWR-R1 prostate cancer cell line inhibited cell growth. Up-regulation of Sox2 was not associated with increased CD133 expression but was associated with increased FGF5 (Fibroblast Growth Factor 5) expression. These data propose a model of elevated Sox2 expression due to loss of AR-mediated repression during castration, and consequent castration-resistance via mechanisms not involving induction of canonical embryonic stem cell pathways. PMID:23326489

  7. ODM-201: a new-generation androgen receptor inhibitor in castration-resistant prostate cancer.

    PubMed

    Fizazi, Karim; Albiges, Laurence; Loriot, Yohann; Massard, Christophe

    2015-01-01

    Androgen deprivation therapy is the standard of care for patients with advanced hormone-sensitive prostate cancer. Despite an initial response, most patients progress to castration-resistant prostate cancer (CRPC). The realization that CRPC remains driven by androgen receptor (AR) signaling has formed the basis for a new generation of agents targeting the AR axis. Two of these agents, abiraterone acetate and enzalutamide, have been shown to prolong overall survival in patients with CRPC. Several other AR inhibitors are currently in development for the treatment of CRPC. The present article reviews ODM-201, a new-generation AR inhibitor with a unique molecular structure, in the treatment of CRPC. The design of an ongoing Phase III trial (ARAMIS) of ODM-201 in men with non-metastatic CRPC is also discussed, at a disease stage for which there is currently no approved treatment. PMID:26313416

  8. Targeting the adaptive molecular landscape of castration-resistant prostate cancer

    PubMed Central

    Wyatt, Alexander W; Gleave, Martin E

    2015-01-01

    Castration and androgen receptor (AR) pathway inhibitors induce profound and sustained responses in advanced prostate cancer. However, the inevitable recurrence is associated with reactivation of the AR and progression to a more aggressive phenotype termed castration-resistant prostate cancer (CRPC). AR reactivation can occur directly through genomic modification of the AR gene, or indirectly via co-factor and co-chaperone deregulation. This mechanistic heterogeneity is further complicated by the stress-driven induction of a myriad of overlapping cellular survival pathways. In this review, we describe the heterogeneous and evolvable molecular landscape of CRPC and explore recent successes and failures of therapeutic strategies designed to target AR reactivation and adaptive survival pathways. We also discuss exciting areas of burgeoning anti-tumour research, and their potential to improve the survival and management of patients with CRPC. PMID:25896606

  9. Novel non-AR therapeutic targets in castrate resistant prostate cancer

    PubMed Central

    Toren, Paul J.

    2013-01-01

    Castrate resistant prostate cancer (CRPC) remains a disease with significant morbidity and mortality. The recent approval of abiraterone and enzalutamide highlight the improvements which can be made targeting the androgen receptor (AR) axis. Nonetheless, resistance inevitably develops and there is continued interest in targeting alternate pathways which cause disease resistance and progression. Here, we review non-AR targets in CRPC, with an emphasis on novel agents now in development. This includes therapeutics which target the tumour microenvironment, the bone metastatic environment, microtubules, cellular energetics, angiogenesis, the stress response, survival proteins, intracellular signal transduction, DNA damage repair and dendritic cells. Understanding the hallmarks of prostate cancer resistance in CRPC has led to the identification and development of these new targets. We review the molecular rationale, as well at the clinical experience for each of these different classes of agents which are in clinical development. PMID:26816739

  10. ODM-201: a new-generation androgen receptor inhibitor in castration-resistant prostate cancer

    PubMed Central

    Fizazi, Karim; Albiges, Laurence; Loriot, Yohann; Massard, Christophe

    2015-01-01

    Androgen deprivation therapy is the standard of care for patients with advanced hormone-sensitive prostate cancer. Despite an initial response, most patients progress to castration-resistant prostate cancer (CRPC). The realization that CRPC remains driven by androgen receptor (AR) signaling has formed the basis for a new generation of agents targeting the AR axis. Two of these agents, abiraterone acetate and enzalutamide, have been shown to prolong overall survival in patients with CRPC. Several other AR inhibitors are currently in development for the treatment of CRPC. The present article reviews ODM-201, a new-generation AR inhibitor with a unique molecular structure, in the treatment of CRPC. The design of an ongoing Phase III trial (ARAMIS) of ODM-201 in men with non-metastatic CRPC is also discussed, at a disease stage for which there is currently no approved treatment. PMID:26313416

  11. Targeting Alternative Sites on the Androgen Receptor to Treat Castration-Resistant Prostate Cancer

    PubMed Central

    Lallous, Nada; Dalal, Kush; Cherkasov, Artem; Rennie, Paul S.

    2013-01-01

    Recurrent, metastatic prostate cancer continues to be a leading cause of cancer-death in men. The androgen receptor (AR) is a modular, ligand-inducible transcription factor that regulates the expression of genes that can drive the progression of this disease, and as a consequence, this receptor is a key therapeutic target for controlling prostate cancer. The current drugs designed to directly inhibit the AR are called anti-androgens, and all act by competing with androgens for binding to the androgen/ligand binding site. Unfortunately, with the inevitable progression of the cancer to castration resistance, many of these drugs become ineffective. However, there are numerous other regulatory sites on this protein that have not been exploited therapeutically. The regulation of AR activity involves a cascade of complex interactions with numerous chaperones, co-factors and co-regulatory proteins, leading ultimately to direct binding of AR dimers to specific DNA androgen response elements within the promoter and enhancers of androgen-regulated genes. As part of the family of nuclear receptors, the AR is organized into modular structural and functional domains with specialized roles in facilitating their inter-molecular interactions. These regions of the AR present attractive, yet largely unexploited, drug target sites for reducing or eliminating androgen signaling in prostate cancers. The design of small molecule inhibitors targeting these specific AR domains is only now being realized and is the culmination of decades of work, including crystallographic and biochemistry approaches to map the shape and accessibility of the AR surfaces and cavities. Here, we review the structure of the AR protein and describe recent advancements in inhibiting its activity with small molecules specifically designed to target areas distinct from the receptor’s androgen binding site. It is anticipated that these new classes of anti-AR drugs will provide an additional arsenal to treat

  12. Tasquinimod in the treatment of castrate-resistant prostate cancer – current status and future prospects

    PubMed Central

    Mehta, Amit R.; Armstrong, Andrew J.

    2016-01-01

    Treatment options have significantly expanded in recent years for men with metastatic castration-resistant prostate cancer (mCRPC), with the routine use of immunotherapy (sipuleucel-T) and novel hormonal agents such as enzalutamide and abiraterone acetate prior to taxane-based chemotherapy or radium-223 radiotherapy. A number of immune checkpoints limit the immune response of the host to metastatic tumor progression in prostate cancer, one of which is an immunosuppressive and pro-angiogenic cell called the myeloid-derived suppressor cell (MDSC). Tasquinimod is a small molecular oral inhibitor of S100A9, a key cell surface regulator of MDSC function, and has shown anti-angiogenic, antitumor and immune-modulatory properties in preclinical models of prostate cancer and other solid tumors. A large randomized phase II trial of tasquinimod in men with chemotherapy-naïve mCRPC demonstrated a significant prolongation in radiographic and symptomatic progression-free survival compared with placebo, which was also associated with improvements in overall survival. Tasquinimod was studied in a global phase III randomized trial in men with bone mCRPC and, while it significantly improved radiographic progression-free survival, this did not result in an overall survival benefit. However, tasquinimod is under evaluation as well as a combination therapy with other systemic agents in prostate cancer and as a single agent in other solid tumors. This review encompasses the preclinical and clinical development of tasquinimod as a therapy for men with prostate cancer. PMID:26834836

  13. Tasquinimod in the treatment of castrate-resistant prostate cancer - current status and future prospects.

    PubMed

    Mehta, Amit R; Armstrong, Andrew J

    2016-02-01

    Treatment options have significantly expanded in recent years for men with metastatic castration-resistant prostate cancer (mCRPC), with the routine use of immunotherapy (sipuleucel-T) and novel hormonal agents such as enzalutamide and abiraterone acetate prior to taxane-based chemotherapy or radium-223 radiotherapy. A number of immune checkpoints limit the immune response of the host to metastatic tumor progression in prostate cancer, one of which is an immunosuppressive and pro-angiogenic cell called the myeloid-derived suppressor cell (MDSC). Tasquinimod is a small molecular oral inhibitor of S100A9, a key cell surface regulator of MDSC function, and has shown anti-angiogenic, antitumor and immune-modulatory properties in preclinical models of prostate cancer and other solid tumors. A large randomized phase II trial of tasquinimod in men with chemotherapy-naïve mCRPC demonstrated a significant prolongation in radiographic and symptomatic progression-free survival compared with placebo, which was also associated with improvements in overall survival. Tasquinimod was studied in a global phase III randomized trial in men with bone mCRPC and, while it significantly improved radiographic progression-free survival, this did not result in an overall survival benefit. However, tasquinimod is under evaluation as well as a combination therapy with other systemic agents in prostate cancer and as a single agent in other solid tumors. This review encompasses the preclinical and clinical development of tasquinimod as a therapy for men with prostate cancer. PMID:26834836

  14. Biallelic Inactivation of BRCA2 in Platinum-sensitive Metastatic Castration-resistant Prostate Cancer.

    PubMed

    Cheng, Heather H; Pritchard, Colin C; Boyd, Thomas; Nelson, Peter S; Montgomery, Bruce

    2016-06-01

    Understanding the molecular underpinnings of sensitivity to specific therapies will advance the goal of precision medicine in prostate cancer (PCa). We identified three patients with metastatic castration-resistant PCa (mCRPC) who achieved an exceptional response to platinum chemotherapy (not first-line treatment for PCa), despite disease progression on prior standard therapies. Using targeted next-generation sequencing on the primary and metastatic tumors, we found that all three patients had biallelic inactivation of BRCA2, a tumor suppressor gene critical for homologous DNA repair. Notably, two had germline BRCA2 mutations, including a patient without compelling family history who was diagnosed at age 66 yr. The third patient had somatic BRCA2 homozygous copy loss. Biallelic BRCA2 inactivation in mCRPC warrants further exploration as a predictive biomarker for sensitivity to platinum chemotherapy. PMID:26724258

  15. Androgen deprivation-induced NCoA2 promotes metastatic and castration-resistant prostate cancer.

    PubMed

    Qin, Jun; Lee, Hui-Ju; Wu, San-Pin; Lin, Shih-Chieh; Lanz, Rainer B; Creighton, Chad J; DeMayo, Francesco J; Tsai, Sophia Y; Tsai, Ming-Jer

    2014-11-01

    A major clinical hurdle for the management of advanced prostate cancer (PCa) in patients is the resistance of tumors to androgen deprivation therapy (ADT) and their subsequent development into castration-resistant prostate cancer (CRPC). While recent studies have identified potential pathways involved in CRPC development, the drivers of CRPC remain largely undefined. Here we determined that nuclear receptor coactivator 2 (NCoA2, also known as SRC-2), which is frequently amplified or overexpressed in patients with metastatic PCa, mediates development of CRPC. In a murine model, overexpression of NCoA2 in the prostate epithelium resulted in neoplasia and, in combination with Pten deletion, promoted the development of metastasis-prone cancer. Moreover, depletion of NCoA2 in PTEN-deficient mice prevented the development of CRPC. In human androgen-sensitive prostate cancer cells, androgen signaling suppressed NCoA2 expression, and NCoA2 overexpression in murine prostate tumors resulted in hyperactivation of PI3K/AKT and MAPK signaling, promoting tumor malignance. Analysis of PCa patient samples revealed a strong correlation among NCoA2-mediated signaling, disease progression, and PCa recurrence. Taken together, our findings indicate that androgen deprivation induces NCoA2, which in turn mediates activation of PI3K signaling and promotes PCa metastasis and CRPC development. Moreover, these results suggest that the inhibition of NCoA2 has potential for PCa therapy. PMID:25295534

  16. Androgen deprivation–induced NCoA2 promotes metastatic and castration-resistant prostate cancer

    PubMed Central

    Qin, Jun; Lee, Hui-Ju; Wu, San-Pin; Lin, Shih-Chieh; Lanz, Rainer B.; Creighton, Chad J.; DeMayo, Francesco J.; Tsai, Sophia Y.; Tsai, Ming-Jer

    2014-01-01

    A major clinical hurdle for the management of advanced prostate cancer (PCa) in patients is the resistance of tumors to androgen deprivation therapy (ADT) and their subsequent development into castration-resistant prostate cancer (CRPC). While recent studies have identified potential pathways involved in CRPC development, the drivers of CRPC remain largely undefined. Here we determined that nuclear receptor coactivator 2 (NCoA2, also known as SRC-2), which is frequently amplified or overexpressed in patients with metastatic PCa, mediates development of CRPC. In a murine model, overexpression of NCoA2 in the prostate epithelium resulted in neoplasia and, in combination with Pten deletion, promoted the development of metastasis-prone cancer. Moreover, depletion of NCoA2 in PTEN-deficient mice prevented the development of CRPC. In human androgen-sensitive prostate cancer cells, androgen signaling suppressed NCoA2 expression, and NCoA2 overexpression in murine prostate tumors resulted in hyperactivation of PI3K/AKT and MAPK signaling, promoting tumor malignance. Analysis of PCa patient samples revealed a strong correlation among NCoA2-mediated signaling, disease progression, and PCa recurrence. Taken together, our findings indicate that androgen deprivation induces NCoA2, which in turn mediates activation of PI3K signaling and promotes PCa metastasis and CRPC development. Moreover, these results suggest that the inhibition of NCoA2 has potential for PCa therapy. PMID:25295534

  17. Cabozantinib inhibits growth of androgen-sensitive and castration-resistant prostate cancer and affects bone remodeling.

    PubMed

    Nguyen, Holly M; Ruppender, Nazanin; Zhang, Xiaotun; Brown, Lisha G; Gross, Ted S; Morrissey, Colm; Gulati, Roman; Vessella, Robert L; Schimmoller, Frauke; Aftab, Dana T; Corey, Eva

    2013-01-01

    Cabozantinib is an inhibitor of multiple receptor tyrosine kinases, including MET and VEGFR2. In a phase II clinical trial in advanced prostate cancer (PCa), cabozantinib treatment improved bone scans in 68% of evaluable patients. Our studies aimed to determine the expression of cabozantinib targets during PCa progression and to evaluate its efficacy in hormone-sensitive and castration-resistant PCa in preclinical models while delineating its effects on tumor and bone. Using immunohistochemistry and tissue microarrays containing normal prostate, primary PCa, and soft tissue and bone metastases, our data show that levels of MET, P-MET, and VEGFR2 are increasing during PCa progression. Our data also show that the expression of cabozantinib targets are particularly pronounced in bone metastases. To evaluate cabozantinib efficacy on PCa growth in the bone environment and in soft tissues we used androgen-sensitive LuCaP 23.1 and castration-resistant C4-2B PCa tumors. In vivo, cabozantinib inhibited the growth of PCa in bone as well as growth of subcutaneous tumors. Furthermore, cabozantinib treatment attenuated the bone response to the tumor and resulted in increased normal bone volume. In summary, the expression pattern of cabozantinib targets in primary and castration-resistant metastatic PCa, and its efficacy in two different models of PCa suggest that this agent has a strong potential for the effective treatment of PCa at different stages of the disease. PMID:24205338

  18. Nelfinavir and Nelfinavir Analogs Block Site-2 Protease Cleavage to Inhibit Castration-Resistant Prostate Cancer

    PubMed Central

    Guan, Min; Su, Leila; Yuan, Yate-Ching; Li, Haiqing; Chow, Warren A.

    2015-01-01

    Nelfinavir and its analogs inhibit proliferation and induce apoptosis of castration-resistant prostate cancer through inhibition of site-2 protease (S2P) activity, which leads to suppression of regulated intramembrane proteolysis. Western blotting in nelfinavir and its analog treated cells confirms accumulation of precursor SREBP-1 and ATF6. Nelfinavir and its analogs inhibit human homolog M. jannaschii S2P cleavage of an artificial protein substrate CED-9 in an in vitro proteolysis assay in a dose-dependent manner. Nelfinavir and its analogs are more potent inhibitors of S2P cleavage activity than 1,10-phenanthroline, a metalloprotease-specific inhibitor. Further, cluster analysis of gene expression from treated DU145 and PC3 cell lines demonstrate a close similarity of nelfinavir, its analogs, and 1,10-phenanthroline. These results show nelfinavir and its analogs inhibit castration-resistant prostate cancer proliferation by blocking regulated intramembrane proteolysis through suppression of S2P cleavage activity. This leads to accumulation of precursor SREBP-1 and ATF6, and development of insufficient reserves of their transcriptionally-active forms. The present results validate S2P and regulated intramembrane proteolysis as novel therapeutic targets for castration-resistant prostate cancer therapeutics. A clinical trial of nelfinavir or its analogs should be developed for castration-resistant prostate cancer. PMID:25880275

  19. The role of radiation therapy in the treatment of metastatic castrate-resistant prostate cancer

    PubMed Central

    Rose, Jim N.

    2015-01-01

    In the setting of castrate-resistant prostate cancer, patients present with a variety of symptoms, including bone metastases, spinal cord compression and advanced pelvic disease. Fortunately, a variety of radiotherapeutic options exist for palliation. This article focuses on these options, including both external beam radiotherapy and radiopharmaceuticals. PMID:26161144

  20. Serum biomarkers of bone metabolism in castration resistant prostate cancer patients with skeletal metastases

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background. Prior studies suggest that elevated markers of bone turnover are prognostic for poor survival in castration resistant prostate cancer (CRPC). The predictive role of these markers relative to bone-targeted therapy is unknown. We prospectively evaluated the prognostic and predictive value ...

  1. Temsirolimus Maintenance Therapy After Docetaxel Induction in Castration-Resistant Prostate Cancer

    PubMed Central

    Booth, Christopher M.; Berry, Scott; Sridhar, Srikala S.; Winquist, Eric; Bandali, Nesan; Chow, Annabelle; Lee, Christina; Xu, Ping; Man, Shan; Kerbel, Robert S.; Ko, Yoo-Joung

    2015-01-01

    Lessons Learned. Temsirolimus maintenance therapy after docetaxel induction chemotherapy is safe in patients with castration-resistant prostate cancer, although biochemical or tumor responses are rare; does not diminish quality of life; and delays radiological and/or symptomatic progression by approximately 6 months. Background. No standard therapy is available for men with castration-resistant prostate cancer (CRPC) who have responded to docetaxel and do not yet have disease progression. Hence, we designed a single-arm phase II trial to explore whether the mTOR inhibitor temsirolimus can maintain the response to docetaxel without compromising quality of life. Methods. After successful docetaxel induction (75 mg/m2 every 3 weeks; 6–10 cycles), 21 CRPC patients underwent temsirolimus maintenance treatment (25 mg weekly; 4 weeks per cycle). The primary endpoint was the time to treatment failure (TTTF) (i.e., radiological and/or symptomatic progression). The secondary endpoints included the tumor response rate (RECIST 1.0), safety (National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0), quality of life (Functional Assessment of Cancer Therapy-Prostate [FACT-P]), pain (Present Pain Intensity [PPI] scale), prostate-specific antigen (PSA) parameters, including time to PSA progression (TTPP) according to Prostate Cancer Clinical Trials Working Group criteria, and serial enumeration of circulating endothelial cells (CECs) and endothelial progenitor cells (CEPs). Results. Patients received a median of 7 cycles of temsirolimus (range, 1–28), resulting in a median TTTF of 24.3 weeks (95% confidence interval [CI], 16.1–33.0), 1 partial tumor response (4.8%), 1 PSA response (4.8%), and a median TTPP of 12.2 weeks (95% CI, 7.8–23.9). Grade 3-4 adverse events were infrequent, and FACT-P and PPI scores remained stable during treatment. CECs did not predict clinical benefit, and CEPs were not consistently detectable. Conclusion. Temsirolimus

  2. Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer

    PubMed Central

    Chang, Kai-Hsiung; Li, Rui; Papari-Zareei, Mahboubeh; Watumull, Lori; Zhao, Yan Daniel; Auchus, Richard J.; Sharifi, Nima

    2011-01-01

    In the majority of cases, advanced prostate cancer responds initially to androgen deprivation therapy by depletion of gonadal testosterone. The response is usually transient, and metastatic tumors almost invariably eventually progress as castration-resistant prostate cancer (CRPC). The development of CRPC is dependent upon the intratumoral generation of the potent androgen, dihydrotestosterone (DHT), from adrenal precursor steroids. Progression to CRPC is accompanied by increased expression of steroid-5α-reductase isoenzyme-1 (SRD5A1) over SRD5A2, which is otherwise the dominant isoenzyme expressed in the prostate. DHT synthesis in CRPC is widely assumed to require 5α-reduction of testosterone as the obligate precursor, and the increased expression of SRD5A1 is thought to reflect its role in converting testosterone to DHT. Here, we show that the dominant route of DHT synthesis in CRPC bypasses testosterone, and instead requires 5α-reduction of androstenedione by SRD5A1 to 5α-androstanedione, which is then converted to DHT. This alternative pathway is operational and dominant in both human CRPC cell lines and fresh tissue obtained from human tumor metastases. Moreover, CRPC growth in mouse xenograft models is dependent upon this pathway, as well as expression of SRD5A1. These findings reframe the fundamental metabolic pathway that drives CRPC progression, and shed light on the development of new therapeutic strategies. PMID:21795608

  3. Raman spectroscopy, a potential tool in diagnosis and prognosis of castration-resistant prostate cancer

    NASA Astrophysics Data System (ADS)

    Wang, Lei; He, Dalin; Zeng, Jin; Guan, Zhenfeng; Dang, Qiang; Wang, Xinyang; Wang, Jun; Huang, Liqing; Cao, Peilong; Zhang, Guanjun; Hsieh, JerTong; Fan, Jinhai

    2013-08-01

    Purpose: We evaluated the feasibility of Raman spectroscopy (RS) in diagnosis and prognosis of castration-resistant prostate cancer (CRPC) in patients with prostate cancer (PC). Materials and methods: Raman spectra are detected from PC cell lines (LNCaP and C4-2) and tissues using a Labram HR 800 RS. Then, principal component analysis (PCA) and support vector machine (SVM) are applied for prediction. A leave-one-out cross-validation is used to train and test the SVM. Results: There are 50 qualified patients, including 33 with androgen-dependent prostate cancer (ADPC) and 17 with CRPC. The spectral changes at 1126, 1170, 1315 to 1338, and 1447 cm-1 between CRPC and ADPC are detected in both cells and tissues models, which are assigned to specific amino acids and DNA. PCA/SVM algorithm provided a sensitivity of 88.2% and a specificity of 87.9% for diagnosing CRPC tissues. Furthermore, 14 patients with ADPC progressed to CRPC within 12 months. These patients are separated into two groups depending on whether their cancers progressed to CRPC within 12 months. PCA/SVM could differentiate these two groups with a sensitivity of 85.7% and a specificity of 88.9%. Conclusions: RS has the potential in diagnosis and prognosis of CRPC in clinical practice.

  4. Targeting TCTP as a New Therapeutic Strategy in Castration-resistant Prostate Cancer

    PubMed Central

    Baylot, Virginie; Katsogiannou, Maria; Andrieu, Claudia; Taieb, David; Acunzo, Julie; Giusiano, Sophie; Fazli, Ladan; Gleave, Martin; Garrido, Carmen; Rocchi, Palma

    2012-01-01

    Heat shock protein 27 (Hsp27) is highly overexpressed in castration-resistant prostate cancer (CRPC) and an antisense inhibitor (OGX-427) is currently in phase II clinical trials. In order to understand mechanisms of action of Hsp27 and find new therapeutic targets specific of CRPC, we screened for Hsp27 client proteins. Here, we report that translationally controlled tumor protein (TCTP) is a new Hsp27 client protein involved in Hsp27 cytoprotection. We found that TCTP expression is absent or weak in normal prostate cells, moderately expressed in 18.5% of treatment naive PC, and becomes uniformly and strongly expressed in 75% of CRPC. To define TCTP function, we developed and worldwide patented a TCTP antisense oligonucleotide (ASO). Interestingly, we found that CRPC progression correlates with TCTP overexpression and loss of P53. TCTP knockdown restored P53 expression and function, suggesting that castration-sensitivity is directly linked to P53 expression. Collectively, these findings provide a new Hsp27 cytoprotection mechanism in CRPC, and preclinical proof-of-concept that combining ASO-mediated TCTP knockdown with castration and/or docetaxel therapy could serve as a novel strategy to treat CRPC, with no or little toxicity for normal prostate cells. PMID:22893039

  5. Drug resistance in castration resistant prostate cancer: resistance mechanisms and emerging treatment strategies

    PubMed Central

    Armstrong, Cameron M; Gao, Allen C

    2015-01-01

    Several mechanisms facilitate the progression of hormone-sensitive prostate cancer to castration-resistant prostate cancer (CRPC). At present, the approved chemotherapies for CRPC include systemic drugs (docetaxel and cabazitaxel) and agents that target androgen signaling, including enzalutamide and abiraterone. While up to 30% of patients have primary resistance to these treatments, each of these drugs confers a significant survival benefit for many. Over time, however, all patients inevitably develop resistance to treatment and their disease will continue to progress. Several key mechanisms have been identified that give rise to drug resistance. Expression of constitutively active variants of the androgen receptor, such as AR-V7, intracrine androgens and overexpression of androgen synthesis enzymes like AKR1C3, and increased drug efflux through ABCB1 are just some of the many discovered mechanisms of drug resistance. Treatment strategies are being developed to target these pathways and reintroduce drug sensitivity. Niclosamide has been discovered to reduce AR-V7 activity and synergized to enzalutamide. Indomethacin has been explored to inhibit AKR1C3 activity and showed to be able to reverse resistance to enzalutamide. ABCB1 transport activity can be mitigated by the phytochemical apigenin and by antiandrogens such as bicalutamide, with each improving cellular response to chemotherapeutics. By better understanding the mechanisms by which drug resistance develops improved treatment strategies will be made possible. Herein, we review the existing knowledge of CRPC therapies and resistance mechanisms as well as methods that have been identified which may improve drug sensitivity. PMID:26309896

  6. A comprehensive review of genomic landscape, biomarkers and treatment sequencing in castration-resistant prostate cancer.

    PubMed

    Seisen, Thomas; Rouprêt, Morgan; Gomez, Florie; Malouf, Gabriel G; Shariat, Shahrokh F; Peyronnet, Benoit; Spano, Jean-Philippe; Cancel-Tassin, Géraldine; Cussenot, Olivier

    2016-07-01

    Hormone-naïve prostate cancer and its castration-resistant state (CRPC) are clinically and genetically heterogeneous diseases. From initiation of prostate carcinogenesis to its evolution towards therapeutic resistance, various combinations of genetic and epigenetic events occur. Schematically, progression to CRPC could be divided in two distinct pathways, either dependent or independent of the androgen receptor activity. Nevertheless, because the better knowledge of the genetic landscape of CRPC is under way, limited clinical applications are available at the moment, underlying the usefulness of prognostic and predictive biomarkers in daily practice. Despite the promising prognostic value of circulating tumor cells, no biomarker has been currently validated as a surrogate for overall survival in CRPC patients. Inversely, considerable interest has been generated with the recent finding of the splice variant AR-V7 that allows to predict resistance to abiraterone acetate and enzalutamide. However, other predictive biomarkers would be necessary to accurately guide personalized sequencing of CRPC treatment, which now includes numerous possibilities based on the six validated drugs, without accounting for those currently under investigation in the ongoing randomized controlled trials. As a consequence, only rational sequencing, which consists in choosing an agent that is not expected to have cross-resistance with previous therapy, can be currently advised. PMID:27327958

  7. Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer.

    PubMed

    Asangani, Irfan A; Dommeti, Vijaya L; Wang, Xiaoju; Malik, Rohit; Cieslik, Marcin; Yang, Rendong; Escara-Wilke, June; Wilder-Romans, Kari; Dhanireddy, Sudheer; Engelke, Carl; Iyer, Mathew K; Jing, Xiaojun; Wu, Yi-Mi; Cao, Xuhong; Qin, Zhaohui S; Wang, Shaomeng; Feng, Felix Y; Chinnaiyan, Arul M

    2014-06-12

    Men who develop metastatic castration-resistant prostate cancer (CRPC) invariably succumb to the disease. Progression to CRPC after androgen ablation therapy is predominantly driven by deregulated androgen receptor (AR) signalling. Despite the success of recently approved therapies targeting AR signalling, such as abiraterone and second-generation anti-androgens including MDV3100 (also known as enzalutamide), durable responses are limited, presumably owing to acquired resistance. Recently, JQ1 and I-BET762 two selective small-molecule inhibitors that target the amino-terminal bromodomains of BRD4, have been shown to exhibit anti-proliferative effects in a range of malignancies. Here we show that AR-signalling-competent human CRPC cell lines are preferentially sensitive to bromodomain and extraterminal (BET) inhibition. BRD4 physically interacts with the N-terminal domain of AR and can be disrupted by JQ1 (refs 11, 13). Like the direct AR antagonist MDV3100, JQ1 disrupted AR recruitment to target gene loci. By contrast with MDV3100, JQ1 functions downstream of AR, and more potently abrogated BRD4 localization to AR target loci and AR-mediated gene transcription, including induction of the TMPRSS2-ERG gene fusion and its oncogenic activity. In vivo, BET bromodomain inhibition was more efficacious than direct AR antagonism in CRPC xenograft mouse models. Taken together, these studies provide a novel epigenetic approach for the concerted blockade of oncogenic drivers in advanced prostate cancer. PMID:24759320

  8. Adaptive responses of androgen receptor signaling in castration-resistant prostate cancer

    PubMed Central

    2015-01-01

    Prostate Cancer (PCa) is an important age-related disease being the most common cancer malignancy and the second leading cause of cancer mortality in men in Western countries. Initially, PCa progression is androgen receptor (AR)- and androgen-dependent. Eventually advanced PCa reaches the stage of Castration-Resistant Prostate Cancer (CRPC), but remains dependent on AR, which indicates the importance of AR activity also for CRPC. Here, we discuss various pathways that influence the AR activity in CRPC, which indicates an adaptation of the AR signaling in PCa to overcome the treatment of PCa. The adaptation pathways include interferences of the normal regulation of the AR protein level, the expression of AR variants, the crosstalk of the AR with cytokine tyrosine kinases, the Src-Akt-, the MAPK-signaling pathways and AR corepressors. Furthermore, we summarize the current treatment options with regard to the underlying molecular basis of the common adaptation processes of AR signaling that may arise after the treatment with AR antagonists, androgen deprivation therapy (ADT) as well as for CRPC, and point towards novel therapeutic strategies. The understanding of individualized adaptation processes in PCa will lead to individualized treatment options in the future. PMID:26325261

  9. PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer.

    PubMed

    Raina, Kanak; Lu, Jing; Qian, Yimin; Altieri, Martha; Gordon, Deborah; Rossi, Ann Marie K; Wang, Jing; Chen, Xin; Dong, Hanqing; Siu, Kam; Winkler, James D; Crew, Andrew P; Crews, Craig M; Coleman, Kevin G

    2016-06-28

    Prostate cancer has the second highest incidence among cancers in men worldwide and is the second leading cause of cancer deaths of men in the United States. Although androgen deprivation can initially lead to remission, the disease often progresses to castration-resistant prostate cancer (CRPC), which is still reliant on androgen receptor (AR) signaling and is associated with a poor prognosis. Some success against CRPC has been achieved by drugs that target AR signaling, but secondary resistance invariably emerges, and new therapies are urgently needed. Recently, inhibitors of bromodomain and extra-terminal (BET) family proteins have shown growth-inhibitory activity in preclinical models of CRPC. Here, we demonstrate that ARV-771, a small-molecule pan-BET degrader based on proteolysis-targeting chimera (PROTAC) technology, demonstrates dramatically improved efficacy in cellular models of CRPC as compared with BET inhibition. Unlike BET inhibitors, ARV-771 results in suppression of both AR signaling and AR levels and leads to tumor regression in a CRPC mouse xenograft model. This study is, to our knowledge, the first to demonstrate efficacy with a small-molecule BET degrader in a solid-tumor malignancy and potentially represents an important therapeutic advance in the treatment of CRPC. PMID:27274052

  10. Therapeutic Targeting of BET Bromodomain Proteins in Castration-Resistant Prostate Cancer

    PubMed Central

    Asangani, Irfan A.; Dommeti, Vijaya L.; Wang, Xiaoju; Malik, Rohit; Cieslik, Marcin; Yang, Rendong; Escara-Wilke, June; Wilder-Romans, Kari; Dhanireddy, Sudheer; Engelke, Carl; Iyer, Mathew K.; Jing, Xiaojun; Wu, Yi-Mi; Cao, Xuhong; Qin, Zhaohui S.; Wang, Shaomeng; Feng, Felix Y.; Chinnaiyan, Arul M.

    2014-01-01

    Men who develop metastatic castration-resistant prostate cancer (CRPC) invariably succumb to the disease. The development and progression to CRPC following androgen ablation therapy is predominantly driven by unregulated androgen receptor (AR) signaling1-3. Despite the success of recently approved therapies targeting AR signaling such as abiraterone4-6 and second generation anti-androgens MDV3100 (enzalutamide)7,8, durable responses are limited, presumably due to acquired resistance. Recently JQ1 and I-BET, two selective small molecule inhibitors that target the amino-terminal bromodomains of BRD4, have been shown to exhibit anti-proliferative effects in a range of malignancies9-12. Here we show that AR signaling-competent CRPC cell lines are preferentially sensitive to BET bromodomain inhibition. BRD4 physically interacts with the N-terminal domain of AR and can be disrupted by JQ111,13. Like the direct AR antagonist, MDV3100, JQ1 disrupted AR recruitment to target gene loci. In contrast to MDV3100, JQ1 functions downstream of AR, and more potently abrogated BRD4 localization to AR target loci and AR-mediated gene transcription including induction of TMPRSS2-ERG and its oncogenic activity. In vivo, BET bromodomain inhibition was more efficacious than direct AR antagonism in CRPC xenograft models. Taken together, these studies provide a novel epigenetic approach for the concerted blockade of oncogenic drivers in advanced prostate cancer. PMID:24759320

  11. The Epothilones: New Therapeutic Agents for Castration-Resistant Prostate Cancer

    PubMed Central

    Dorff, Tanya B.

    2011-01-01

    The management of castration-resistant prostate cancer (CRPC) presents a clinical challenge because of limitations in efficacy and durability with currently available therapeutics. The epothilones represent a novel class of anticancer therapy that stabilizes microtubules, causing cell death and tumor regression in preclinical models. The structure of the tubulin-binding site for epothilones is distinct from that of the taxanes. Moreover, preclinical studies suggest nonoverlapping mechanisms of resistance between epothilones and taxanes. In early-phase studies in patients with CRPC, treatment with ixabepilone, a semisynthetic analog of epothilone B, induced objective responses and prostate-specific antigen declines in men previously progressing on docetaxel-based regimens. Clinical activity has been observed in nonrandomized trials for patients with CRPC using ixabepilone in the first- and second-line settings as a single agent and in combination with estramustine. Patupilone and sagopilone were also shown to have promising efficacy in phase II clinical trials of patients with CRPC. All three epothilones appear to be well tolerated, with modest rates of neutropenia and peripheral neuropathy. The lack of crossresistance between epothilones and taxanes may allow sequencing of these agents. Evaluating epothilones in phase III comparative trials would provide much-needed insight into their potential place in the management of patients with CRPC. PMID:21964003

  12. PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer

    PubMed Central

    Raina, Kanak; Lu, Jing; Qian, Yimin; Altieri, Martha; Gordon, Deborah; Rossi, Ann Marie K.; Wang, Jing; Chen, Xin; Dong, Hanqing; Siu, Kam; Winkler, James D.; Crew, Andrew P.; Crews, Craig M.; Coleman, Kevin G.

    2016-01-01

    Prostate cancer has the second highest incidence among cancers in men worldwide and is the second leading cause of cancer deaths of men in the United States. Although androgen deprivation can initially lead to remission, the disease often progresses to castration-resistant prostate cancer (CRPC), which is still reliant on androgen receptor (AR) signaling and is associated with a poor prognosis. Some success against CRPC has been achieved by drugs that target AR signaling, but secondary resistance invariably emerges, and new therapies are urgently needed. Recently, inhibitors of bromodomain and extra-terminal (BET) family proteins have shown growth-inhibitory activity in preclinical models of CRPC. Here, we demonstrate that ARV-771, a small-molecule pan-BET degrader based on proteolysis-targeting chimera (PROTAC) technology, demonstrates dramatically improved efficacy in cellular models of CRPC as compared with BET inhibition. Unlike BET inhibitors, ARV-771 results in suppression of both AR signaling and AR levels and leads to tumor regression in a CRPC mouse xenograft model. This study is, to our knowledge, the first to demonstrate efficacy with a small-molecule BET degrader in a solid-tumor malignancy and potentially represents an important therapeutic advance in the treatment of CRPC. PMID:27274052

  13. Androgen Deprivation Therapy and Secondary Hormone Therapy in the Management of Hormone-sensitive and Castration-resistant Prostate Cancer.

    PubMed

    Saad, Fred; Fizazi, Karim

    2015-11-01

    Androgen deprivation therapy (ADT) is the standard of care for patients with metastatic prostate cancer (mPC). However, nearly all patients with mPC progress to castration-resistant PC (CRPC). Arrays of treatments, including secondary hormonal therapies, are available for the treatment of mPC and CRPC, which show efficacy when administered with ADT. Continuation of ADT is recommended for CRPC treatment as therapies are added. New secondary hormonal therapies include abiraterone, targeting the CYP17 enzyme family, and enzalutamide, an androgen receptor inhibitor with heightened binding specificity. The optimal decision-making process for CRPC treatment option remains unclear, pending further research and experience. PMID:26282624

  14. Updated recommendations from the Spanish Oncology Genitourinary Group for the treatment of patients with metastatic castration-resistant prostate cancer.

    PubMed

    Climent, Miguel Ángel; León-Mateos, Luis; González Del Alba, Aránzazu; Pérez-Valderrama, Begoña; Méndez-Vidal, M José; Mellado, Begoña; Arranz, José Ángel; Sánchez-Hernández, Alfredo; Cassinello, Javier; Olmos, David; Carles, Joan

    2015-11-01

    Prostate cancer is the most prevalent male urogenital malignancy. Approximately 30% of patients with prostate cancer will develop advanced disease. Androgen deprivation therapy achieves disease control in about 90% of these patients, but the majority of them will eventually develop progressive disease, a status called castration-resistant prostate carcinoma (CRPC). However, in recent years, several new therapy strategies, such as immunotherapy, hormonal manipulations, chemotherapy agents and some bone-targeted therapies, have demonstrated an improvement in terms of overall survival in controlled trials. In 2012, the Spanish Oncology Genitourinary Group (SOGUG) published its recommendations for the treatment of patients with CRPC. Due to the recent appearance of important new data and the complexity of decision-making in this field, SOGUG herein provides updated recommendations for the treatment of patients with metastatic prostate cancer. PMID:26100652

  15. Crosstalk between RON and androgen receptor signaling in the development of castration resistant prostate cancer

    PubMed Central

    Batth, Izhar; Yun, Huiyoung; Hussain, Suleman; Meng, Peng; Osumulski, Powel; Huang, Tim Hui-Ming; Bedolla, Roble; Profit, Amanda; Reddick, Robert; Kumar, Addanki

    2016-01-01

    Castrate-resistant prostate cancer (CRPC) is the fatal form of prostate cancer. Although reactivation of androgen receptor (AR) occurs following androgen deprivation, the precise mechanism involved is unclear. Here we show that the receptor tyrosine kinase, RON alters mechanical properties of cells to influence epithelial to mesenchymal transition and functions as a transcription factor to differentially regulate AR signaling. RON inhibits AR activation and subset of AR-regulated transcripts in androgen responsive LNCaP cells. However in C4-2B, a castrate-resistant sub-line of LNCaP and AR-negative androgen independent DU145 cells, RON activates subset of AR-regulated transcripts. Expression of AR in PC-3 cells leads to activation of RON under androgen deprivation but not under androgen proficient conditions implicating a role for RON in androgen independence. Consistently, RON expression is significantly elevated in castrate resistant prostate tumors. Taken together our results suggest that RON activation could aid in promoting androgen independence and that inhibition of RON in combination with AR antagonist(s) merits serious consideration as a therapeutic option during hormone deprivation therapy. PMID:26872377

  16. The Role of Palliative Surgery in Castration-Resistant Prostate Cancer.

    PubMed

    Heidenreich, Axel; Porres, Daniel; Pfister, David

    2015-01-01

    Androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone (LHRH) analogues or antagonists represents the treatment of choice in men with metastatic prostate cancer (PCA). Depending on the serum concentration of the prostate-specific antigen (PSA) nadir, the survival might vary between 11 and 78 months. In castration-resistant PCA (CRPC), all new medical treatment options can induce complete and partial remissions in metastatic foci, but they have no profound effect on the prostate itself, as has been shown recently. About one-third of all patients without local treatment of the primary will develop significant complications of the lower and upper urinary tract due to local progression of the PCA. In men with CRPC and lower urinary tract symptoms, palliative transurethral resection of the prostate (TURP) can be performed with a 60-70% success rate. Infiltration of the pelvic floor, the bladder neck and trigone, and the external urethral sphincter can make palliative radical surgery necessary. Bladder neck closure with continent vesicostomy, radical cystoprostatectomy with an incontinent urinary diversion, and anterior and posterior exenteration are individual therapeutic options in men with a good performance status and a considerable life expectancy. Symptomatic involvement of the upper urinary tract can be managed by the placement of endoluminal stents or a percutaneous nephrostomy in men with poor performance. In men with a good response to ADT and a good performance status, reconstructive ureteral surgery might be considered and the options of ureteral reimplantation, ureter ileal replacement, and a subcutaneous pyelovesical bypass have to be discussed. The indication to perform one of the above-mentioned surgical approaches needs to be discussed in a multidisciplinary tumor board. PMID:26632812

  17. Expert opinion on first-line therapy in the treatment of castration-resistant prostate cancer.

    PubMed

    Maroto, Pablo; Solsona, Eduardo; Gallardo, Enrique; Mellado, Begoña; Morote, Juan; Arranz, José Ángel; Gómez-Veiga, Francisco; Unda, Miguel; Climent, Miguel Ángel; Alcaraz, Antonio

    2016-04-01

    Treatment of metastatic castration-resistant prostate cancer (mCRPC) has been revolutionized in recent years. It is well known that androgen receptor is still active in most patients with disease progression and serum testosterone levels <50 ng/dL. Moreover, further hormonal maneuvers, either through decreasing androgen levels (abiraterone) or by targeting the androgen receptor (AR) pathway (enzalutamide), prolong survival. In addition, a new cytostatic able to overcome docetaxel resistance, cabazitaxel, and the radioisotope radium 223 have been incorporated to the armamentarium of mCRPC. mCRPC is not only a heterogeneous tumor, it changes over time developing neuroendocrine features or selection of clones resistant to hormonal maneuvers. In addition, the multiplicity of current treatments, make it necessary to design algorithms that help the specialist to choose the most appropriate treatment for a particular patient. The lack of randomized trials comparing face to face the different available options limit the scope of this review. In this article, the authors describe the prognostic factors for first line therapy in patients with mCRPC, and propose a treatment algorithm for mCRPC based on the levels of scientific evidence available and, if not available, on the consensus between medical professionals. Finally, the panel discuss how to define progressive disease in the setting of mCRPC and treatment with targeted therapies. PMID:26363809

  18. Novel Imidazopyridine Derivatives Possess Anti-Tumor Effect on Human Castration-Resistant Prostate Cancer Cells

    PubMed Central

    Muniyan, Sakthivel; D’Cunha, Napoleon; Robinson, Tashika; Hoelting, Kyle; Dwyer, Jennifer G.; Bu, Xiu R.; Batra, Surinder K.; Lin, Ming-Fong

    2015-01-01

    Prostate cancer (PCa) is the second leading cause of cancer-related death afflicting United States males. Most treatments to-date for metastatic PCa include androgen-deprivation therapy and second-generation anti-androgens such as abiraterone acetate and enzalutamide. However, a majority of patients eventually develop resistance to these therapies and relapse into the lethal, castration-resistant form of PCa to which no adequate treatment option remains. Hence, there is an immediate need to develop effective therapeutic agents toward this patient population. Imidazopyridines have recently been shown to possess Akt kinase inhibitory activity; thus in this study, we investigated the inhibitory effect of novel imidazopyridine derivatives HIMP, M-MeI, OMP, and EtOP on different human castration-resistant PCa cells. Among these compounds, HIMP and M-MeI were found to possess selective dose- and time-dependent growth inhibition: they reduced castration-resistant PCa cell proliferation and spared benign prostate epithelial cells. Using LNCaP C-81 cells as the model system, these compounds also reduced colony formation as well as cell adhesion and migration, and M-MeI was the most potent in all studies. Further investigation revealed that while HIMP primarily inhibits PCa cell growth via suppression of PI3K/Akt signaling pathway, M-MeI can inhibit both PI3K/Akt and androgen receptor pathways and arrest cell growth in the G2 phase. Thus, our results indicate the novel compound M-MeI to be a promising candidate for castration-resistant PCa therapy, and future studies investigating the mechanism of imidazopyridine inhibition may aid to the development of effective anti-PCa agents. PMID:26121643

  19. Abiraterone Treatment in Castration-Resistant Prostate Cancer Selects for Progesterone Responsive Mutant Androgen Receptors

    PubMed Central

    Chen, Eddy J.; Sowalsky, Adam G.; Gao, Shuai; Cai, Changmeng; Voznesensky, Olga; Schaefer, Rachel; Loda, Massimo; True, Lawrence D.; Ye, Huihui; Troncoso, Patricia; Lis, Rosina L.; Kantoff, Philip W.; Montgomery, Robert B.; Nelson, Peter S.; Bubley, Glenn J.; Balk, Steven P.; Taplin, Mary-Ellen

    2014-01-01

    Purpose The CYP17A1 inhibitor abiraterone markedly reduces androgen precursors and is thereby effective in castration-resistant prostate cancer (CRPC). However, abiraterone increases progesterone, which can activate certain mutant androgen receptors (ARs) identified previously in flutamide-resistant tumors. Therefore, we sought to determine if CYP17A1 inhibitor treatment selects for progesterone activated mutant ARs. Experimental Design AR was examined by targeted sequencing in metastatic tumor biopsies from 18 CRPC patients who were progressing on a CYP17A1 inhibitor (17 on abiraterone, 1 on ketoconazole), alone or in combination with dutasteride, and by whole exome sequencing in residual tumor in one patient treated with neoadjuvant leuprolide plus abiraterone. Results The progesterone-activated T878A mutant AR was present at high allele frequency in 3 of the 18 CRPC cases. It was also present in one focus of resistant tumor in the neoadjuvant treated patient, but not in a second clonally related resistant focus which instead had lost one copy of PTEN and both copies of CHD1. The T878A mutation appeared to be less common in the subset of CRPC patients treated with abiraterone plus dutasteride, and transfection studies showed that dutasteride was a more potent direct antagonist of the T878A versus the wildtype AR. Conclusions These findings indicate that selection for tumor cells expressing progesterone-activated mutant ARs is a mechanism of resistance to CYP17A1 inhibition. PMID:25320358

  20. FOXA1 regulates androgen receptor variant activity in models of castrate-resistant prostate cancer

    PubMed Central

    Nakjang, Sirintra; Chaytor, Lewis; Grey, James; Robson, Craig N.; Gaughan, Luke

    2015-01-01

    Retention of androgen receptor (AR) signalling in castrate-resistant prostate cancer (CRPC) highlights the requirement for the development of more effective AR targeting therapies. A key mechanism of resistance to anti-androgens is through expression of constitutively active AR variants (AR-Vs) that are refractory to next-generation therapies, including Enzalutamide and Abiraterone. By maintaining an androgenic gene signature, AR-Vs drive tumour survival and progression in castrate conditions. Critically, however, our understanding of the mechanics of AR-V-driven transcription is limited, particularly with respect to dependency on pioneer factor function. Here we show that depletion of FOXA1 in the CWR22Rv1 CRPC cell line abrogates the oncogenic potential of AR-Vs. Gene expression profiling reveals that approximately 41% of the AR-V transcriptome requires FOXA1 and that depletion of FOXA1 attenuates AR-V binding at a sub-set of analysed co-regulated genes. Interestingly, AR-V levels are elevated in cells depleted of FOXA1 as a consequence of attenuated negative feedback on the AR gene, but is insufficient to maintain cell growth as evidenced by marked anti-proliferative effects in FOXA1 knockdown cells. In all, our data suggests that AR-Vs are dependent on FOXA1 for sustaining a pro-proliferative gene signature and agents targeting FOXA1 may represent novel therapeutic options for CRPC patients. PMID:26336819

  1. Cabazitaxel in castration resistant prostate cancer with brain metastases: 3 case reports.

    PubMed

    De Placido, Sabino; Rescigno, Pasquale; Federico, Piera; Buonerba, Carlo; Bosso, Davide; Puglia, Livio; Izzo, Michela; Policastro, Tania; Di Lorenzo, Giuseppe

    2014-06-16

    Prostate cancer is the most common non-cutaneous malignancy for men. The skeleton is the most common metastatic site but, following an improvement in survival, metastases in uncommon sites are being found more frequently in clinical practice, especially brain metastases. Despite the new drugs now available for metastatic castration resistant prostate cancer, no clinical evidence exists about their effectiveness on brain metastases. We describe the clinical history of 3 patients treated with cabazitaxel plus whole brain radiotherapy. These case reports demonstrate that cabazitaxel is highly active and well tolerated in brain metastases. PMID:24945013

  2. Cabazitaxel in castration resistant prostate cancer with brain metastases: 3 case reports

    PubMed Central

    Placido, Sabino De; Rescigno, Pasquale; Federico, Piera; Buonerba, Carlo; Bosso, Davide; Puglia, Livio; Izzo, Michela; Policastro, Tania; Lorenzo, Giuseppe Di

    2014-01-01

    Prostate cancer is the most common non-cutaneous malignancy for men. The skeleton is the most common metastatic site but, following an improvement in survival, metastases in uncommon sites are being found more frequently in clinical practice, especially brain metastases. Despite the new drugs now available for metastatic castration resistant prostate cancer, no clinical evidence exists about their effectiveness on brain metastases. We describe the clinical history of 3 patients treated with cabazitaxel plus whole brain radiotherapy. These case reports demonstrate that cabazitaxel is highly active and well tolerated in brain metastases. PMID:24945013

  3. Therapy decisions for the symptomatic patient with metastatic castration-resistant prostate cancer

    PubMed Central

    Markowski, Mark C; Pienta, Kenneth J

    2015-01-01

    Metastatic prostate cancer continues to kill approximately 30,000 men per year. Since 2010, five new therapeutic agents have been Food and Drug Administration (FDA) approved to treat metastatic castration-resistant prostate cancer (mCRPC). With the increasing number of therapies available to clinicians, the most effective sequence in which to implement these treatments remains unknown. The presence or absence of symptoms (i.e., bony pain, visceral crisis) is a key parameter that informs the decision-making process regarding therapy. Treatment algorithms based on: 1) asymptomatic/minimal symptoms, 2) moderate symptoms or chemotherapy ineligible or 3) symptomatic disease need to be developed. PMID:25865849

  4. Androgen receptor targeted therapies in castration-resistant prostate cancer: Bench to clinic.

    PubMed

    Imamura, Yusuke; Sadar, Marianne D

    2016-08-01

    The androgen receptor is a transcription factor and validated therapeutic target for prostate cancer. Androgen deprivation therapy remains the gold standard treatment, but it is not curative, and eventually the disease will return as lethal castration-resistant prostate cancer. There have been improvements in the therapeutic landscape with new agents approved, such as abiraterone acetate, enzalutamide, sipuleucel-T, cabazitaxel and Ra-223, in the past 5 years. New insight into the mechanisms of resistance to treatments in advanced disease is being and has been elucidated. All current androgen receptor-targeting therapies inhibit the growth of prostate cancer by blocking the ligand-binding domain, where androgen binds to activate the receptor. Persuasive evidence supports the concept that constitutively active androgen receptor splice variants lacking the ligand-binding domain are one of the resistant mechanisms underlying advanced disease. Transcriptional activity of the androgen receptor requires a functional AF-1 region in its N-terminal domain. Preclinical evidence proved that this domain is a druggable target to forecast a potential paradigm shift in the management of advanced prostate cancer. This review presents an overview of androgen receptor-related mechanisms of resistance as well as novel therapeutic agents to overcome resistance that is linked to the expression of androgen receptor splice variants in castration-resistant prostate cancer. PMID:27302572

  5. Prostate Cancer Stem-like Cells Contribute to the Development of Castration-Resistant Prostate Cancer

    PubMed Central

    Ojo, Diane; Lin, Xiaozeng; Wong, Nicholas; Gu, Yan; Tang, Damu

    2015-01-01

    Androgen deprivation therapy (ADT) has been the standard care for patients with advanced prostate cancer (PC) since the 1940s. Although ADT shows clear benefits for many patients, castration-resistant prostate cancer (CRPC) inevitably occurs. In fact, with the two recent FDA-approved second-generation anti-androgens abiraterone and enzalutamide, resistance develops rapidly in patients with CRPC, despite their initial effectiveness. The lack of effective therapeutic solutions towards CRPC largely reflects our limited understanding of the underlying mechanisms responsible for CRPC development. While persistent androgen receptor (AR) signaling under castration levels of serum testosterone (<50 ng/mL) contributes to resistance to ADT, it is also clear that CRPC evolves via complex mechanisms. Nevertheless, the physiological impact of individual mechanisms and whether these mechanisms function in a cohesive manner in promoting CRPC are elusive. In spite of these uncertainties, emerging evidence supports a critical role of prostate cancer stem-like cells (PCSLCs) in stimulating CRPC evolution and resistance to abiraterone and enzalutamide. In this review, we will discuss the recent evidence supporting the involvement of PCSLC in CRPC acquisition as well as the pathways and factors contributing to PCSLC expansion in response to ADT. PMID:26593949

  6. End points of clinical trials in metastatic castration-resistant prostate cancer: A systematic review

    PubMed Central

    Colloca, Giuseppe; Venturino, Antonella; Governato, Ilaria

    2014-01-01

    AIM: To review the definition and performance of the commonly used end points in trials of systemic therapies in metastatic castration-resistant prostate cancer patients. METHODS: A literature search was undertaken on PubMed database to identify studies meeting established criteria, with the aim of selecting randomized clinical trials and study definition and performance of their end points. The end points were grouped into three categories: overall survival (OS), time-to-event end points, and response end points. A special analysis was performed for secondary end points of the studies which documented a benefit in OS in the experimental arm. Finally, publishes analyses for surrogacy of the included end points were also reported. RESULTS: OS, time-to-event and response end points in 31 selected trials were analyzed. OS was the primary end point in 14 trials, and the secondary end point in 17. A time-to-event end point was the primary end point in 8 studies, and the secondary end point in 22; the most reported time-to-event end points were composite end points, and the events changed among trials. A response end point was the primary end point in 9 studies, in 3 it was prostate-specific antigen (PSA)-related, in 3 pain-related and in 3 mixed. A response end point was the secondary end point in 19 studies: PSA response and radiologic response were the most frequently used secondary end points in 19 and 11 trials, respectively, while pain response was used in 5 studies. CONCLUSION: A homogeneous definition of progression in future trials is mandatory. Among response end points, pain-response and PSA-response appear to be the most reliable. PMID:25332911

  7. Emerging Therapeutic for the Treatment of Skeletal-related Events Associated With Metastatic Castrate-resistant Prostate Cancer

    PubMed Central

    Sieber, Paul R

    2014-01-01

    Prostate cancer is the most prevalent cancer in US and European men and the second leading cause of cancer death in those populations. It is somewhat unique in that nearly all patients who succumb to the disease will ultimately develop bone metastasis. Morbidity from bone metastasis-referred to as skeletal-related events, which include fractures, cord compression, radiation to bone, and surgery to bone—leads to significant costs and impaired quality of life. This article reviews three agents and the roles they play in the ever-changing armamentarium of treatments for metastatic castrate-resistant prostate cancer (mCRPC). The potential benefits of these agents are discussed, as well as the continuing use of these agents and their earlier introduction in the patient with progressive mCRPC with bone metastasis. PMID:24791151

  8. Non-Coding RNAs in Castration-Resistant Prostate Cancer: Regulation of Androgen Receptor Signaling and Cancer Metabolism

    PubMed Central

    Shih, Jing-Wen; Wang, Ling-Yu; Hung, Chiu-Lien; Kung, Hsing-Jien; Hsieh, Chia-Ling

    2015-01-01

    Hormone-refractory prostate cancer frequently relapses from therapy and inevitably progresses to a bone-metastatic status with no cure. Understanding of the molecular mechanisms conferring resistance to androgen deprivation therapy has the potential to lead to the discovery of novel therapeutic targets for type of prostate cancer with poor prognosis. Progression to castration-resistant prostate cancer (CRPC) is characterized by aberrant androgen receptor (AR) expression and persistent AR signaling activity. Alterations in metabolic activity regulated by oncogenic pathways, such as c-Myc, were found to promote prostate cancer growth during the development of CRPC. Non-coding RNAs represent a diverse family of regulatory transcripts that drive tumorigenesis of prostate cancer and various other cancers by their hyperactivity or diminished function. A number of studies have examined differentially expressed non-coding RNAs in each stage of prostate cancer. Herein, we highlight the emerging impacts of microRNAs and long non-coding RNAs linked to reactivation of the AR signaling axis and reprogramming of the cellular metabolism in prostate cancer. The translational implications of non-coding RNA research for developing new biomarkers and therapeutic strategies for CRPC are also discussed. PMID:26690121

  9. Non-Coding RNAs in Castration-Resistant Prostate Cancer: Regulation of Androgen Receptor Signaling and Cancer Metabolism.

    PubMed

    Shih, Jing-Wen; Wang, Ling-Yu; Hung, Chiu-Lien; Kung, Hsing-Jien; Hsieh, Chia-Ling

    2015-01-01

    Hormone-refractory prostate cancer frequently relapses from therapy and inevitably progresses to a bone-metastatic status with no cure. Understanding of the molecular mechanisms conferring resistance to androgen deprivation therapy has the potential to lead to the discovery of novel therapeutic targets for type of prostate cancer with poor prognosis. Progression to castration-resistant prostate cancer (CRPC) is characterized by aberrant androgen receptor (AR) expression and persistent AR signaling activity. Alterations in metabolic activity regulated by oncogenic pathways, such as c-Myc, were found to promote prostate cancer growth during the development of CRPC. Non-coding RNAs represent a diverse family of regulatory transcripts that drive tumorigenesis of prostate cancer and various other cancers by their hyperactivity or diminished function. A number of studies have examined differentially expressed non-coding RNAs in each stage of prostate cancer. Herein, we highlight the emerging impacts of microRNAs and long non-coding RNAs linked to reactivation of the AR signaling axis and reprogramming of the cellular metabolism in prostate cancer. The translational implications of non-coding RNA research for developing new biomarkers and therapeutic strategies for CRPC are also discussed. PMID:26690121

  10. GRP78-targeted nanotherapy against castrate-resistant prostate cancer cells expressing membrane GRP78.

    PubMed

    Delie, Florence; Petignat, Patrick; Cohen, Marie

    2013-12-01

    Glucose-regulated protein 78, GRP78, is a chaperone protein mainly located in the endoplasmic reticulum (ER) of normal cells. In stress conditions, GRP78 is overexpressed and in different cancer cell types, it is expressed at the cell surface, whereas it stays intracellular in non-cancerous cells. Therefore, it appears as a strategic target to recognize malignant cells. Prostate cancer is one of the most diagnosed cancers in men. The development of castrate resistant tumors and the resistance to chemotherapy frequently occur. The carboxy-terminal ER retention domain is defined by the KDEL amino acid sequence. We developed anti-KDEL functionalized polymeric nanoparticles (NPs) loaded with paclitaxel (Tx) to specifically target prostate cancer cells expressing GRP78. The sensitivity to Tx in different formulations was compared in three prostate cell lines: PNT1B, a normal cell line, PC3, a cancer cell line faintly expressing GRP78 at its surface, and DU145, a cancer cell line expressing GRP78 at its cell surface. Our results show that the targeted formulation significantly increases Tx sensitivity of cell line expressing GRP78 at its surface compared to other treatments suggesting the added value of GRP78 targeted therapy for castrate resistant tumor which expresses GRP78 at its cell surface. PMID:23090204

  11. Prostaglandin receptor EP3 mediates growth inhibitory effect of aspirin through androgen receptor and contributes to castration resistance in prostate cancer cells.

    PubMed

    Kashiwagi, Eiji; Shiota, Masaki; Yokomizo, Akira; Itsumi, Momoe; Inokuchi, Junichi; Uchiumi, Takeshi; Naito, Seiji

    2013-06-01

    Although numerous epidemiological studies show aspirin to reduce risk of prostate cancer, the mechanism of this effect is unclear. Here, we first confirmed that aspirin downregulated androgen receptor (AR) and prostate-specific antigen in prostate cancer cells. We also found that aspirin upregulated prostaglandin receptor subtype EP3 but not EP2 or EP4. The EP3 antagonist L798106 and EP3 knockdown increased AR expression and cell proliferation, whereas the EP3 agonist sulprostone decreased them, indicating that EP3 affects AR expression. Additionally, EP3 (PTGER3) transcript levels were significantly decreased in human prostate cancer tissues compared with those in normal human prostate tissues, suggesting that EP3 is important to prostate carcinogenesis. Decreased EP3 expression was also seen in castration-resistant subtype CxR cells compared with parental LNCaP cells. Finally, we found that aspirin and EP3 modulators affected prostate cancer cell growth. Taken together, aspirin suppressed LNCaP cell proliferation via EP3 signaling activation; EP3 downregulation contributed to prostate carcinogenesis and to progression from androgen-dependent prostate cancer to castration-resistant prostate cancer by regulating AR expression. In conclusion, cyclooxygenases and EP3 may represent attractive therapeutic molecular targets in androgen-dependent prostate cancer. PMID:23493387

  12. Phase II trial of weekly Docetaxel, Zoledronic acid, and Celecoxib for castration-resistant prostate cancer.

    PubMed

    Kattan, Joseph; Bachour, Marwan; Farhat, Fadi; El Rassy, Elie; Assi, Tarek; Ghosn, Marwan

    2016-08-01

    Background Treatment options for patients with metastatic castration-resistance prostate cancer are unsatisfactory. Docetaxel monotherapy offers promising results with a tolerable toxicity profile. However, enhancing the clinical index of Docetaxel-based therapy remains the ultimate goal. Methods We conducted a phase II, open label, multinational prospective trial to evaluate the efficacy of weekly Docetaxel combined with Zoledronic acid and Celecoxib. Eligible patients received 25 mg/m(2) Docetaxel weekly for 3 consecutive weeks every 4 weeks, 4 mg Zoledronic acid every 4 weeks, and 200 mg oral Celecoxib twice daily. Enrollment was terminated prematurely upon the publication of reports of cardiac toxicity associated with cyclooxygenase (COX) 2 inhibitors. Results Our study enrolled 22 patients with a median of 4.7 cycles per patient. The median overall survival (OS) was 9.8 months (range 0.7 to 24.1 months) with 36 % and 4.5 % survival rates at 1 and 2 years, respectively. Our patients had a biologic response in 40.1 % of cases and a palliative response in 72.7 %. Among the eight patients with measurable disease, three had partial responses, two had stable disease, and three had progressive disease, leading to a response rate (RR) of 62.5 %. The observed toxicities were mild and limited to grade 3 events. Nine patients had anemia (40.1 %), 5 had sensory neuropathy (22.7 %) and 2 had stomatitis (9.1 %). Conclusion The combination of Docetaxel, Celecoxib, and Zoledronic acid failed to improve OS or to offer an acceptable biologic response. We do not believe that there is compelling evidence to include either Celecoxib or Zoledronic acid in further phase II/III trials. PMID:27159981

  13. Optimal Sequencing of New Drugs in Metastatic Castration-Resistant Prostate Cancer: Dream or Reality?

    PubMed

    Caffo, Orazio; Lunardi, Andrea; Trentin, Chiara; Maines, Francesca; Veccia, Antonello; Galligioni, Enzo

    2016-01-01

    The availability of new drugs capable of improving the overall survival of patients with metastatic castration-resistant prostate cancer has led to the possibility of using them sequentially in the hope of obtaining a cumulative survival benefit. The new agents have already been administered as third-line treatments in patients who have previously received them as second line in everyday clinical practice, but the efficacy of this practice is not yet supported by clinical trial data, and evidence of possible cross-resistance has reinforced the debate concerning the best sequence to use in order to maximise the benefit. Furthermore, the situation is further complicated by the possibility of administering new hormonal agents to chemotherapy-naïve patients, and novel chemotherapeutic agents to hormone-sensitive patients. This article critically reviews the available data concerning the sequential use of new drugs, and discusses the real evidence concerning their optimal positioning in the therapeutic strategy of metastatic castration-resistant prostate cancer. PMID:26721408

  14. New radiopharmaceutical agents for the treatment of castration-resistant prostate cancer.

    PubMed

    Maffioli, L; Florimonte, L; Costa, D C; Correia Castanheira, J; Grana, C; Luster, M; Bodei, L; Chinol, M

    2015-12-01

    Prostate cancer (PCa) is the fourth most common cancer worldwide in terms of incidence and third among male, but is becoming the most common cancer in developed countries. In many patients the disease will progress despite of castration levels of testosterone, to become castration-resistant PCa (CRPC). Nearly all patients with CRPC show bone metastases. The treatment of patients with bony metastases has dramatically changed during the past three years because of new therapeutic approaches addressed to obtain pain control, reduced skeletal morbidity, and most importantly, increased survival rate. A possible therapy can be based also on the use of radiopharmaceuticals systemically administered to slow or reverse the bone metastatic progression. In facts bone-homing radiopharmaceuticals are taken up in areas of high bone turnover, including areas with high osteoblastic activity. Recently, a bone targeting radiopharmaceutical, Radium-223 dichloride was added to this group of drugs clearly representing a new generation of radiopharmaceutical in bone therapy. Clinical trials had shown that the treatment with Ra-223 allowed the reduction of the risk of death respect to placebo. No other radiometabolic treatment achieved such result, evidentiating the disease-modifying properties of this bone-homing radiopharmaceutical. In an effort to treat patients with disseminated PCa, who became resistant to hormonal therapy, molecular targets have been recently identified. Prostate specific membrane antigen (PSMA) is one attractive target for diagnosis and therapy of metastasized PCa since its expression levels are directly correlated to androgen independence, metastasis, and progression. Gastrin-releasing peptide receptors (GRPr) are also highly overexpressed in PCa. Numerous studies suggest the possibility of a high PCa-specific signal with radiolabeled bombesin analogs targeting GRPr. Low molecular weight peptides directed against these molecular targets have been radiolabeled

  15. Multiplexed quantum dot labeling of activated c-Met signaling in castration-resistant human prostate cancer.

    PubMed

    Hu, Peizhen; Chu, Gina C-Y; Zhu, Guodong; Yang, Hua; Luthringer, Daniel; Prins, Gail; Habib, Fouad; Wang, Yuzhuo; Wang, Ruoxiang; Chung, Leland W K; Zhau, Haiyen E

    2011-01-01

    The potential application of multiplexed quantum dot labeling (MQDL) for cancer detection and prognosis and monitoring therapeutic responses has attracted the interests of bioengineers, pathologists and cancer biologists. Many published studies claim that MQDL is effective for cancer biomarker detection and useful in cancer diagnosis and prognosis, these studies have not been standardized against quantitative biochemical and molecular determinations. In the present study, we used a molecularly characterized human prostate cancer cell model exhibiting activated c-Met signaling with epithelial to mesenchymal transition (EMT) and lethal metastatic progression to bone and soft tissues as the gold standard, and compared the c-Met cell signaling network in this model, in clinical human prostate cancer tissue specimens and in a castration-resistant human prostate cancer xenograft model. We observed c-Met signaling network activation, manifested by increased phosphorylated c-Met in all three. The downstream survival signaling network was mediated by NF-κB and Mcl-1 and EMT was driven by receptor activator of NF-κB ligand (RANKL), at the single cell level in clinical prostate cancer specimens and the xenograft model. Results were confirmed by real-time RT-PCR and western blots in a human prostate cancer cell model. MQDL is a powerful tool for assessing biomarker expression and it offers molecular insights into cancer progression at both the cell and tissue level with high degree of sensitivity. PMID:22205960

  16. Targeting DNA repair with combination veliparib (ABT-888) and temozolomide in patients with metastatic castration-resistant prostate cancer

    PubMed Central

    Carducci, Michael A.; Slovin, Susan; Cetnar, Jeremy; Qian, Jiang; McKeegan, Evelyn M.; Refici-Buhr, Marion; Chyla, Brenda; Shepherd, Stacie P.; Giranda, Vincent L.; Alumkal, Joshi J.

    2015-01-01

    Summary Androgen receptor-mediated transcription is directly coupled with the induction of DNA damage, and castration-resistant tumor cells exhibit increased activity of poly (ADP-ribose) polymerase (PARP)-1, a DNA repair enzyme. This study assessed the efficacy and safety of low dose oral PARP inhibitor veliparib (ABT-888) and temozolomide (TMZ) in docetaxel-pretreated patients with metastatic castration-resistant prostate cancer (mCRPC) in a single-arm, open-label, pilot study. Patients with mCRPC progressing on at least one docetaxel-based therapy and prostate specific antigen (PSA) ≥2 ng/mL were treated with veliparib 40 mg twice daily on days 1–7 and TMZ once daily (150 mg/m2/day cycle 1; if well tolerated then 200 mg/m2/day cycle 2 onwards) on days 1–5 q28 days. Patients received 2 (median) treatment cycles (range, 1–9). The primary end-point was confirmed PSA response rate (decline≥30 %). Twenty-six eligible patients were enrolled, 25 evaluable for PSA response. Median baseline PSA was 170 ng/mL. Two patients had a confirmed PSA response (8.0 %; 95 % CI: 1.0– 26.0), 13 stable PSA, and 10 PSA progression. The median progression-free survival was 9 weeks (95 % CI: 7.9–17) and median overall survival 39.6 weeks (95 % CI: 26.6–not estimable). The most frequent treatment-emergent adverse events (AEs) were thrombocytopenia (77 %), anemia (69 %), fatigue (50 %), neutropenia (42 %), nausea (38 %), and constipation (23 %). Grade 3/4 AEs occurring in >10 % of patients were thrombocytopenia (23 %) and anemia (15 %). Veliparib and TMZ combination was well tolerated but with modest activity. Biomarker analysis supported the proof of concept that this combination has some antitumor activity in mCRPC. PMID:24764124

  17. Cabazitaxel as second-line or third-line therapy in patients with metastatic castration-resistant prostate cancer.

    PubMed

    Kongsted, Per; Svane, Inge M; Lindberg, Henriette; Bisbjerg, Rasmus; Daugaard, Gedske; Sengeløv, Lisa

    2016-08-01

    To compare treatment outcomes in patients with metastatic castration-resistant prostate cancer treated with cabazitaxel (CA) as second-line or third-line therapy in the everyday clinical setting. Charts from 94 patients treated with CA as second-line (n=28) or third-line therapy (n=66) were evaluated. Common Terminology Criteria for Adverse Events were used to register grade 3-4 nonhematological toxicity during treatment with CA. Baseline metastatic castration-resistant prostate cancer-related prognostic factors, duration of therapy, and maximum prostate-specific antigen (PSA) percentage change were registered during treatment with CA and previous/subsequent novel androgen receptor targeting therapies. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. A median of 6 versus 5 treatment cycles was administered in patients treated with second-line and third-line CA (P=0.483). Events with grade 3-4 nonhematological toxicity were equally distributed in the two groups (32 vs. 35%, P=0.80). PSA responses were observed in 46 and 17% of patients treated with second-line and third-line CA (P=0.002). PFS (5.5 vs. 3.3 months, P=0.087, log rank) and OS (18.3 vs. 11.4 months, P=0.003, log rank) was longer in patients treated with second-line CA. OS measured from second-line abiraterone acetate/enzalutamide was similar (18.0 months) to second-line CA (P=0.883, log rank). Treatment-related toxicity was independent of CA being administered as second-line or third-line therapy. Although PFS and the frequency of PSA responders favored patients treated with second-line CA, one treatment sequence could not be considered superior to the other in this study. PMID:27148775

  18. A Phase I Study of Everolimus and Docetaxel in Patients With Castration-Resistant Prostate Cancer

    PubMed Central

    Courtney, Kevin D.; Manola, Judith B.; Elfiky, Aymen A.; Ross, Robert; Oh, William K.; Yap, Jeffrey T.; Van den Abbeele, Annick D.; Ryan, Christopher W.; Beer, Tomasz M.; Loda, Massimo; Priolo, Carmen; Kantoff, Philip; Taplin, Mary-Ellen

    2015-01-01

    Activation of the phosphoinositide 3-kinase signaling cascade, often through loss of the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) tumor suppressor, is frequent in castration-resistant prostate cancer (CRPC). We assessed the safety and efficacy of combining the mammalian target of rapamycin (mTOR) inhibitor everolimus with docetaxel in a phase I clinical trial of men with metastatic CRPC, and evaluated the ability of fluorine–18-fluorodeoxyglucose (FDG) positron emission tomography (PET) to predict response to treatment. The observed clinical activity of tolerable dose levels of everolimus with docetaxel was low. FDG-PET might serve as a biomarker for target inhibition by mTOR inhibitors in metastatic CRPC. Background The PTEN tumor suppressor is frequently lost in CRPC, with activation of Akt-mTOR signaling, driving growth. We conducted a phase I trial of the mTOR inhibitor, everolimus, and docetaxel in CRPC. Patients and Methods Eligible patients had progressive, metastatic, chemotherapy-naive CRPC. Patients received everolimus 10 mg daily for 2 weeks and underwent a restaging FDG-PET/computed tomography scan. Patient cohorts were subsequently treated at 3 dose levels of everolimus with docetaxel: 5 mg to 60 mg/m2, 10 mg to 60 mg/m2, and 10 mg to 70 mg/m2. The primary end point was the safety and tolerability of combination therapy. Results Accrual was 4 patients at level 1, 3 patients at level 2, and 8 patients at level 3. Common toxicities were hematologic and fatigue. Serum concentrations of everolimus when administered with docetaxel were 1.5 to 14.8 ng/mL in patients receiving 5 mg everolimus and 4.5 to 55.4 ng/mL in patients receiving 10 mg everolimus. Four patients had partial metabolic response (PMR) using FDG-PET, 12 had stable metabolic disease, and 2 had progressive metabolic disease after a 2-week treatment with everolimus alone. Five of 12 evaluable patients experienced a prostate-specific antigen (PSA) reduction ≥ 50

  19. Improving the outcome of patients with castration-resistant prostate cancer through rational drug development

    PubMed Central

    Attard, G; Sarker, D; Reid, A; Molife, R; Parker, C; de Bono, J S

    2006-01-01

    Castration-resistant prostate cancer (CRPC) is now the second most common cause of male cancer-related mortality. Although docetaxel has recently been shown to extend the survival of patients with CRPC in two large randomised phase III studies, subsequent treatment options remain limited for these patients. A greater understanding of the molecular causes of castration resistance is allowing a more rational approach to the development of new drugs and many new agents are now in clinical development. Therapeutic targets include the adrenal steroid synthesis pathway, androgen receptor signalling, the epidermal growth factor receptor family, insulin growth factor-1 receptor, histone deacetylase, heat shock protein 90 and the tumour vasculature. Drugs against these targets are giving an insight into the molecular pathogenesis of this disease and promise to improve patient quality of life and survival. Finally, the recent discovery of chromosomal translocations resulting in the upregulation of one of at least 3 ETS genes (ERG, ETV1, ETV4) may lead to novel agents for the treatment of this disease. PMID:16983403

  20. Cholesterol biosynthesis inhibitor RO 48-8071 suppresses growth of hormone-dependent and castration-resistant prostate cancer cells

    PubMed Central

    Liang, Yayun; Mafuvadze, Benford; Aebi, Johannes D; Hyder, Salman M

    2016-01-01

    Standard treatment for primary prostate cancer includes systemic exposure to chemotherapeutic drugs that target androgen receptor or antihormone therapy (chemical castration); however, drug-resistant cancer cells generally emerge during treatment, limiting the continued use of systemic chemotherapy. Patients are then treated with more toxic standard therapies. Therefore, there is an urgent need for novel and more effective treatments for prostate cancer. The cholesterol biosynthetic pathway is an attractive therapeutic target for treating endocrine-dependent cancers because cholesterol is an essential structural and functional component of cell membranes as well as the metabolic precursor of endogenous steroid hormones. In this study, we have examined the effects of RO 48-8071 (4′-[6-(allylmethylamino)hexyloxy]-4-bromo-2′-fluorobenzophenone fumarate; Roche Pharmaceuticals internal reference: RO0488071) (RO), which is an inhibitor of 2, 3-oxidosqualene cyclase (a key enzyme in the cholesterol biosynthetic pathway), on prostate cancer cells. Exposure of both hormone-dependent and castration-resistant human prostate cancer cells to RO reduced prostate cancer cell viability and induced apoptosis in vitro. RO treatment reduced androgen receptor protein expression in hormone-dependent prostate cancer cells and increased estrogen receptor β (ERβ) protein expression in both hormone-dependent and castration-resistant prostate cancer cell lines. Combining RO with an ERβ agonist increased its ability to reduce castration-resistant prostate cancer cell viability. In addition, RO effectively suppressed the growth of aggressive castration-resistant human prostate cancer cell xenografts in vivo without any signs of toxicity to experimental animals. Importantly, RO did not reduce the viability of normal prostate cells in vitro. Our study is the first to demonstrate that the cholesterol biosynthesis inhibitor RO effectively suppresses growth of human prostate cancer cells

  1. Response to 223Ra-dichloride in castration-resistant prostate cancer with bone metastasis: A case report

    PubMed Central

    Cabrera, Montserrat Estorch; Rey, Pablo Maroto; Carrió, Ignasi; Montes, Alberto; López, Diego Alonso

    2016-01-01

    Painful bone metastases are common in prostate cancer, with current treatments including non-steroidal analgesics and opiates, surgery, external beam radiotherapy and bone-targeting β-emitting radiopharmaceuticals. The α-emitting isotope 223Ra-dichloride (Ra-223) has been associated with improved overall survival and increased time to first skeletal-related events in patients with castration-resistant prostate cancer (CRPC) presenting with symptomatic bone metastases. The current study reports the case of a 70-year-old male patient, who was diagnosed with prostate cancer in 1999 upon presentation with increased prostate-specific antigen (PSA) levels and painful bone metastases in the context of CRPC. In November 2010, subsequent to undergoing hormonal blockage, the patient was treated with ketoconazole (200 mg/8 h) followed by 10 cycles of docetaxel (75 mg/m2 every 3 weeks). Following disease progression, the patient received 6 doses of Ra-223 (50 kBq/kg; 1 dose/4 weeks). During this treatment period, an improvement in the patient's symptoms, and levels of bone alkaline phosphatase (BAP) and PSA were noted. Furthermore, Ra-223 was well-tolerated without any relevant bone marrow toxicity. However, 2 months after the administration of the final dose of Ra-223, PSA and BAP levels increased again, and bone pain deteriorated. A bone scan showed stable disease in the previously observed metastatic lesions; however, new lesions simultaneously appeared in different locations, indicating progressive disease. PMID:27446432

  2. Systemic Medical Treatment in Men with Metastatic Castration-Resistant Prostate Cancer: Recommendations for Daily Routine.

    PubMed

    Herden, Jan; Heidegger, Isabell; Paffenholz, Pia; Porres, Daniel

    2015-01-01

    The approval or clinical evaluation of several new agents - cabazitaxel, abiraterone acetate, enzalutamide, sipuleucel-T, and radium-223 - has significantly changed the management of patients with metastatic castration-resistant prostate cancer (mCRPC) prior to or after docetaxel-based chemotherapy. All of these agents have resulted in a significant survival benefit as compared to their control group. However, treatment responses might differ depending on the associated comorbidities and the extent and biological aggressiveness of the disease. Furthermore, treatment-associated side effects differ between the various drugs. As new drugs become approved, new treatment strategies and markers to best select which patients will best respond to which drug are needed. It is the aim of the current article to i) summarize the data of established treatment options in mCRPC, ii) highlight new developments in medical treatment, iii) provide clinically useful algorithms for the daily routine, and iv) point out future developments in medical treatment. PMID:26633646

  3. Improving Taxane-Based Chemotherapy in Castration-Resistant Prostate Cancer.

    PubMed

    Kroon, Jan; Kooijman, Sander; Cho, Nam-Joon; Storm, Gert; van der Pluijm, Gabri

    2016-06-01

    Currently, the clinical utility of taxane-based drug formulations in castration-resistant prostate cancer (CRPC) is severely limited by acquired chemotherapy resistance, dose-limiting toxicities, and nonresponders. Therefore, approaches to improve taxane-based chemotherapy are desperately required. In this review, we highlight the strategies that aim to overcome these limitations, such as bypassing therapy resistance, targeted drug delivery, and adequate prediction of therapy response. The involvement of the apoptotic pathway, ABC transporters, the glucocorticoid receptor (GR) axis, androgen receptor (AR) splicing, epithelial plasticity, and cancer stem cells in mediating taxane-resistance are outlined. Furthermore, passive and active targeted nanomedicinal drug delivery strategies and the use of circulating tumor cells in predicting docetaxel responses are discussed. Finally, recent advances towards clinical translation of these approaches in CRPC are reviewed. PMID:27068431

  4. HDAC inhibition impedes epithelial-mesenchymal plasticity and suppresses metastatic, castration-resistant prostate cancer.

    PubMed

    Ruscetti, M; Dadashian, E L; Guo, W; Quach, B; Mulholland, D J; Park, J W; Tran, L M; Kobayashi, N; Bianchi-Frias, D; Xing, Y; Nelson, P S; Wu, H

    2016-07-21

    PI3K (phosphoinositide 3-kinase)/AKT and RAS/MAPK (mitogen-activated protein kinase) pathway coactivation in the prostate epithelium promotes both epithelial-mesenchymal transition (EMT) and metastatic castration-resistant prostate cancer (mCRPC), which is currently incurable. To study the dynamic regulation of the EMT process, we developed novel genetically defined cellular and in vivo model systems from which epithelial, EMT and mesenchymal-like tumor cells with Pten deletion and Kras activation can be isolated. When cultured individually, each population has the capacity to regenerate all three tumor cell populations, indicative of epithelial-mesenchymal plasticity. Despite harboring the same genetic alterations, mesenchymal-like tumor cells are resistant to PI3K and MAPK pathway inhibitors, suggesting that epigenetic mechanisms may regulate the EMT process, as well as dictate the heterogeneous responses of cancer cells to therapy. Among differentially expressed epigenetic regulators, the chromatin remodeling protein HMGA2 is significantly upregulated in EMT and mesenchymal-like tumors cells, as well as in human mCRPC. Knockdown of HMGA2, or suppressing HMGA2 expression with the histone deacetylase inhibitor LBH589, inhibits epithelial-mesenchymal plasticity and stemness activities in vitro and markedly reduces tumor growth and metastasis in vivo through successful targeting of EMT and mesenchymal-like tumor cells. Importantly, LBH589 treatment in combination with castration prevents mCRPC development and significantly prolongs survival following castration by enhancing p53 and androgen receptor acetylation and in turn sensitizing castration-resistant mesenchymal-like tumor cells to androgen deprivation therapy. Taken together, these findings demonstrate that cellular plasticity is regulated epigenetically, and that mesenchymal-like tumor cell populations in mCRPC that are resistant to conventional and targeted therapies can be effectively treated with the

  5. HDAC Inhibition Impedes Epithelial-Mesenchymal Plasticity and Suppresses Metastatic, Castration-Resistant Prostate Cancer

    PubMed Central

    Ruscetti, Marcus; Dadashian, Eman L.; Guo, Weilong; Quach, Bill; Mulholland, David J.; Park, Juw Won; Tran, Linh M.; Kobayashi, Naoko; Bianchi-Frias, Daniella; Xing, Yi; Nelson, Peter S.; Wu, Hong

    2015-01-01

    PI3K/AKT and RAS/MAPK pathway co-activation in the prostate epithelium promotes both epithelial-mesenchymal transition (EMT) and metastatic castration-resistant prostate cancer (mCRPC), which is currently incurable. To study the dynamic regulation of the EMT process, we developed novel genetically-defined cellular and in vivo model systems from which epithelial, EMT, and mesenchymal-like tumor cells with Pten deletion and Kras activation can be isolated. When cultured individually, each population has the capacity to regenerate all three tumor cell populations, indicative of epithelial-mesenchymal plasticity. Despite harboring the same genetic alterations, mesenchymal-like tumor cells are resistant to PI3K and MAPK pathway inhibitors, suggesting that epigenetic mechanisms may regulate the EMT process, as well as dictate the heterogeneous responses of cancer cells to therapy. Among differentially expressed epigenetic regulators, the chromatin remodeling protein HMGA2 is significantly upregulated in EMT and mesenchymal-like tumors cells, as well as in human mCRPC. Knockdown of HMGA2, or suppressing HMGA2 expression with the histone deacetylase (HDAC) inhibitor LBH589, inhibits epithelial-mesenchymal plasticity and stemness activities in vitro and dramatically reduces tumor growth and metastasis in vivo through successful targeting of EMT and mesenchymal-like tumor cells. Importantly, LBH589 treatment in combination with castration prevents mCRPC development and significantly prolongs survival following castration by enhancing p53 and AR acetylation and in turn sensitizing castration-resistant mesenchymal-like tumor cells to ADT. Taken together, these findings demonstrate that cellular plasticity is regulated epigenetically, and that mesenchymal-like tumor cell populations in mCRPC that are resistant to conventional and targeted therapies can be effectively treated with the epigenetic inhibitor LBH589. PMID:26640144

  6. Pain in castration-resistant prostate cancer with bone metastases: a qualitative study

    PubMed Central

    2011-01-01

    Background Bone metastases are a common painful and debilitating consequence of castration-resistant prostate cancer (CPRC). Bone pain may predict patients' prognosis and there is a need to further explore CRPC patients' experiences of bone pain in the overall context of disease pathology. Due to the subjective nature of pain, assessments of pain severity, onset and progression are reliant on patient assessment. Patient reported outcome (PRO) measures, therefore, are commonly used as key endpoints for evaluating the efficacy of CRPC treatments. Evidence of the content validity of leading PRO measures of pain severity used in CRPC clinical trials is, however, limited. Methods To document patients' experience of CRPC symptoms including pain, and their impact on health-related quality of life (HRQL), semi-structured in-depth qualitative interviews were conducted with 17 patients with CRPC and bone metastases. The content validity of the Present Pain Intensity (PPI) scale from the McGill Pain Questionnaire (MPQ), and the 'Average Pain' and 'Worst Pain' items of the Brief Pain Inventory Short-Form (BPI-SF) was also assessed. Results Patients with CRPC and bone metastases present with a constellation of symptoms that can have a profound effect on HRQL. For patients in this study, bone pain was the most prominent and debilitating symptom associated with their condition. Bone pain was chronic and, despite being generally well-managed by analgesic medication, instances of breakthrough cancer pain (BTcP) were common. Cognitive debriefing of the selected PRO measures of pain severity highlighted difficulties among patients in understanding the verbal response scale (VRS) of the MPQ PPI scale. There were also some inconsistencies in the way in which the BPI-SF 'Average Pain' item was interpreted by patients. In contrast, the BPI-SF 'Worst Pain' item was well understood and interpreted consistently among patients. Conclusions Study findings support the importance of PRO

  7. Importance of cycles of chemotherapy and postdocetaxel novel therapies in metastatic castration-resistant prostate cancer

    PubMed Central

    Poon, Darren M.C.; Ng, Joyce; Chan, Kuen

    2015-01-01

    Purpose With the emergence of various novel therapies including new generation taxane and androgen-targeted therapies, the optimal sequence of systemic treatment in metastatic castration-resistant prostate cancer (mCRPC) patients remains to be defined. Our aim is to investigate the impact of duration of docetaxel-based chemotherapy and postdocetaxel treatment in mCRPC patients. Methods The medical data of 57 Chinese mCRPC patients who received docetaxel-based chemotherapy in two oncology centers between 2003 and 2012 were reviewed. The treatment efficacy and toxicity were determined. The potential determinants of efficacy were also determined. Results Fifty-seven patients (median age 66 years, range 51–82 years) were given docetaxel-based chemotherapy, of whom 48 (84.2%) received 3-weekly docetaxel (52.5–75 mg/m2) and nine (15.8%) received weekly docetaxel (35 mg/m2). Postdocetaxel treatments were received by 31 (57.4%) patients, including abiraterone in 13 patients and cabazitaxel in one patient. The median follow-up time was 14.3 months. The median overall survival (OS) and progression-free survival were 20.8 months and 5.8 months, respectively. In multivariate analysis, eight cycles or more of chemotherapy [hazard ratio (HR) = 0.151, P < 0.0358], use of postdocetaxel treatment (HR = 0.346, P = 0.0005), and hemoglobin level of <10 (HR = 5.224, P < 0.0001) were independent determinants of OS. Patients who had received abiraterone and cabazitaxel as postdocetaxel treatment had significantly longer OS compared with those who received other postdocetaxel treatments (including rechallenge of docetaxel) and those who did not receive any postdocetaxel treatment (35.3 months vs. 20.8 months vs. 15.3 months, P = 0.00057). Conclusions The results suggest that maximizing exposure to docetaxel-based chemotherapy followed by novel therapies would have a favorable survival impact on mCRPC patients. PMID:26157768

  8. The hippo pathway effector YAP regulates motility, invasion, and castration-resistant growth of prostate cancer cells.

    PubMed

    Zhang, Lin; Yang, Shuping; Chen, Xingcheng; Stauffer, Seth; Yu, Fang; Lele, Subodh M; Fu, Kai; Datta, Kaustubh; Palermo, Nicholas; Chen, Yuanhong; Dong, Jixin

    2015-04-01

    Yes-associated protein (YAP) is an effector of the Hippo tumor suppressor pathway. The functional significance of YAP in prostate cancer has remained elusive. In this study, we first show that enhanced expression of YAP is able to transform immortalized prostate epithelial cells and promote migration and invasion in both immortalized and cancerous prostate cells. We found that YAP mRNA was upregulated in androgen-insensitive prostate cancer cells (LNCaP-C81 and LNCaP-C4-2 cells) compared to the level in androgen-sensitive LNCaP cells. Importantly, ectopic expression of YAP activated androgen receptor signaling and was sufficient to promote LNCaP cells from an androgen-sensitive state to an androgen-insensitive state in vitro, and YAP conferred castration resistance in vivo. Accordingly, YAP knockdown greatly reduced the rates of migration and invasion of LNCaP-C4-2 cells and under androgen deprivation conditions largely blocked cell division in LNCaP-C4-2 cells. Mechanistically, we found that extracellular signal-regulated kinase-ribosomal s6 kinase signaling was downstream of YAP for cell survival, migration, and invasion in androgen-insensitive cells. Finally, immunohistochemistry showed significant upregulation and hyperactivation of YAP in castration-resistant prostate tumors compared to their levels in hormone-responsive prostate tumors. Together, our results identify YAP to be a novel regulator in prostate cancer cell motility, invasion, and castration-resistant growth and as a potential therapeutic target for metastatic castration-resistant prostate cancer (CRPC). PMID:25645929

  9. Determining the frequency of pathogenic germline variants from exome sequencing in patients with castrate-resistant prostate cancer

    PubMed Central

    Hart, Steven N; Ellingson, Marissa S; Schahl, Kim; Vedell, Peter T; Carlson, Rachel E; Sinnwell, Jason P; Barman, Poulami; Sicotte, Hugues; Eckel-Passow, Jeanette E; Wang, Liguo; Kalari, Krishna R; Qin, Rui; Kruisselbrink, Teresa M; Jimenez, Rafael E; Bryce, Alan H; Tan, Winston; Weinshilboum, Richard; Wang, Liewei; Kohli, Manish

    2016-01-01

    Objectives To determine the frequency of pathogenic inherited mutations in 157 select genes from patients with metastatic castrate-resistant prostate cancer (mCRPC). Design Observational. Setting Multisite US-based cohort. Participants Seventy-one adult male patients with histological confirmation of prostate cancer, and had progressive disease while on androgen deprivation therapy. Results Twelve patients (17.4%) showed evidence of carrying pathogenic or likely pathogenic germline variants in the ATM, ATR, BRCA2, FANCL, MSR1, MUTYH, RB1, TSHR and WRN genes. All but one patient opted in to receive clinically actionable results at the time of study initiation. We also found that pathogenic germline BRCA2 variants appear to be enriched in mCRPC compared to familial prostate cancers. Conclusions Pathogenic variants in cancer-susceptibility genes are frequently observed in patients with mCRPC. A substantial proportion of patients with mCRPC or their family members would derive clinical utility from mutation screening. Trial registration number NCT01953640; Results. PMID:27084275

  10. Cabazitaxel: A novel taxane for metastatic castration-resistant prostate cancer-current implications and future prospects

    PubMed Central

    Abidi, Afroz

    2013-01-01

    Recent advances in the management of prostate cancer have shown considerable development with time and many novel therapeutic agents have been approved over the past years. For patients with metastatic castration-resistant prostate cancer (mCRPC), initially docetaxel was the standard chemotherapy but once they became refractory to docetaxel, no treatment improved survival. This scenario changed in June 2010 when the US Food and Drug Administration (FDA) approved Cabazitaxel as a new therapeutic option for patients with mCRPC resistant to docetaxel. Cabazitaxel, being a novel tubulin-binding taxane with poor affinity for P-glycoprotein, decreases the chances of resistance. It has shown antitumor activity in preclinical, phase I, II and III clinical studies in docetaxel-resistant tumors. This article summarises the background, pharmacodynamic, kinetics and clinical development of cabazitaxel for the treatment of castration-resistant prostate cancer. Future development and rational use of this drug in other tumors is under therapeutic investigation. PMID:24250198

  11. Therapeutic Options and Multifaceted Treatment Paradigms In Metastatic Castrate Resistant Prostate Cancer

    PubMed Central

    Vaishampayan, Ulka

    2014-01-01

    Purpose of Review The field of prostate cancer therapeutics has undergone a rapid and dramatic change in the last few years. Multiple agents with very distinct mechanisms of actions and unique toxicities and efficacies have become available for clinical use. The focus of this review is to give a summary of clinical perspectives of the indications, including pros and cons of the currently approved regimens. The next generation of novel targets and agents are also highlighted. Recent Findings Addition of docetaxel based chemotherapy to conventional androgen suppression therapy in hormone sensitive advanced prostate cancer demonstrated overall survival benefit in recently released results of ECOG 3805. In castrate resistant metastatic disease, development of novel immunotherapy (Sipuleucel T), chemotherapy (docetaxel and cabazitaxel), radiation (alpharadin) and hormone therapy (abiraterone and enzalutamide) agents has created a range of choices for treatment, palliation and improved life expectancy. Summary A paradigm shift has occurred in the management of advanced prostate cancer, with multiple novel agents addressing distinct pathways, and demonstrating powerful efficacy. The judicious use of the available agents, with finesse of sequencing, and concomitant palliative care has prolonged survival and made living with the disease more reasonable and tolerable. PMID:24626129

  12. Whole Transcriptome Sequencing Reveals Extensive Unspliced mRNA in Metastatic Castration-Resistant Prostate Cancer

    PubMed Central

    Sowalsky, Adam G.; Xia, Zheng; Wang, Liguo; Zhao, Hao; Chen, Shaoyong; Bubley, Glenn J.; Balk, Steven P.; Li, Wei

    2014-01-01

    Men with metastatic prostate cancer (PCa) who are treated with androgen deprivation therapies (ADT) usually relapse within 2–3 years with disease that is termed castration-resistant prostate cancer (CRPC). To identify the mechanism that drives these advanced tumors, paired-end RNA-sequencing (RNA-seq) was performed on a panel of CRPC bone marrow biopsy specimens. From this genome-wide approach, mutations were found in a series of genes with PCa relevance including: AR, NCOR1, KDM3A, KDM4A, CHD1, SETD5, SETD7, INPP4B, RASGRP3, RASA1, TP53BP1 and CDH1, and a novel SND1:BRAF gene fusion. Amongst the most highly-expressed transcripts were ten non-coding RNAs (ncRNAs), including MALAT1 and PABPC1, which are involved in RNA processing. Notably, a high percentage of sequence reads mapped to introns, which were determined to be the result of incomplete splicing at canonical splice junctions. Using quantitative PCR (qPCR) a series of genes (AR, KLK2, KLK3, STEAP2, CPSF6, and CDK19) were confirmed to have a greater proportion of unspliced RNA in CRPC specimens than in normal prostate epithelium, untreated primary PCa, and cultured PCa cells. This inefficient coupling of transcription and mRNA splicing suggests an overall increase in transcription or defect in splicing. PMID:25189356

  13. MOR209/ES414, a Novel Bispecific Antibody Targeting PSMA for the Treatment of Metastatic Castration-Resistant Prostate Cancer.

    PubMed

    Hernandez-Hoyos, Gabriela; Sewell, Toddy; Bader, Robert; Bannink, Jeannette; Chenault, Ruth A; Daugherty, Mollie; Dasovich, Maria; Fang, Hang; Gottschalk, Rebecca; Kumer, John; Miller, Robert E; Ravikumar, Padma; Wiens, Jennifer; Algate, Paul A; Bienvenue, David; McMahan, Catherine J; Natarajan, Sateesh K; Gross, Jane A; Blankenship, John W

    2016-09-01

    Treatment of metastatic, castration-resistant prostate cancer (mCRPC) remains a highly unmet medical need and current therapies ultimately result in disease progression. Immunotherapy is a rapidly growing approach for treatment of cancer but has shown limited success to date in the treatment of mCRPC. We have developed a novel humanized bispecific antibody, MOR209/ES414, built on the ADAPTIR (modular protein technology) platform, to redirect T-cell cytotoxicity toward prostate cancer cells by specifically targeting T cells through CD3ε to prostate cancer cells expressing PSMA (prostate-specific membrane antigen). In vitro cross-linking of T cells with PSMA-expressing tumor cells by MOR209/ES414 triggered potent target-dependent tumor lysis and induction of target-dependent T-cell activation and proliferation. This activity occurred at low picomolar concentrations of MOR209/ES414 and was effective at low T-effector to tumor target cell ratios. In addition, cytotoxic activity was equivalent over a wide range of PSMA expression on target cells, suggesting that as few as 3,700 PSMA receptors per cell are sufficient for tumor lysis. In addition to high sensitivity and in vitro activity, MOR209/ES414 induced limited production of cytokines compared with other bispecific antibody formats. Pharmacokinetic analysis of MOR209/ES414 demonstrated a serum elimination half-life in NOD/SCID γ (NSG) mice of 4 days. Administration of MOR209/ES414 in murine xenograft models of human prostate cancer significantly inhibited tumor growth, prolonged survival, and decreased serum prostate-specific antigen levels only in the presence of adoptively transferred human T cells. On the basis of these preclinical findings, MOR209/ES414 warrants further investigation as a potential therapeutic for the treatment of CRPC. Mol Cancer Ther; 15(9); 2155-65. ©2016 AACR. PMID:27406985

  14. A Phase 2 Trial of Abiraterone Acetate in Japanese Men with Metastatic Castration-resistant Prostate Cancer and without Prior Chemotherapy (JPN-201 Study)

    PubMed Central

    Matsubara, Nobuaki; Uemura, Hirotsugu; Satoh, Takefumi; Suzuki, Hiroyoshi; Nishiyama, Tsutomu; Uemura, Hiroji; Hashine, Katsuyoshi; Imanaka, Keiichiro; Ozono, Seiichiro; Akaza, Hideyuki

    2014-01-01

    Objective Abiraterone acetate has been approved in >70 countries for chemotherapy-naïve metastatic castration-resistant prostate cancer patients. Efficacy and safety of abiraterone acetate (1000 mg/once daily) with prednisolone (5 mg/twice daily) in chemotherapy-naïve Japanese patients with metastatic castration-resistant prostate cancer was evaluated. Methods Men, ≥20 years, with prostate-specific antigen levels of ≥5 ng/ml and evidence of progression were enrolled in this Phase 2, multicenter, open-label study. Primary efficacy endpoint was proportion of patients achieving a prostate-specific antigen decline of ≥50% from baseline (prostate-specific antigen response) after 12 week of treatment. Secondary efficacy endpoints and safety were assessed. Results A confirmed prostate-specific antigen response was observed in 29/48 (60.4%) patients by week 12; lower limit of two-sided 90% confidence interval was >35% (threshold response rate), demonstrating efficacy of abiraterone acetate. Secondary efficacy endpoints: prostate-specific antigen response rate during treatment period: 62.5%; objective radiographic response, partial response: 4/18 (22.2%) patients; complete response: none; stable disease: 11/18 (61.1%) patients; median percent change in prostate-specific antigen level from baseline at Week 12: −66.62%. Median prostate-specific antigen response duration and progression-free survival were not reached, and median radiographic progression-free survival was 253 days. Of 31/48 (64.6%) patients experienced adverse events of special interest; most common was hepatic function abnormality (37.5%, Grade 3: 10.4%). One Grade 3 hypertension was the only mineralocorticoid adverse event >Grade 1/2. Conclusions Efficacy of abiraterone acetate plus prednisolone was demonstrated by decline in prostate-specific antigen levels with evidence of antitumor activity by radiography in Japanese patients with chemotherapy-naïve metastatic castration-resistant prostate

  15. Radium-223 for the treatment of castration-resistant prostate cancer

    PubMed Central

    El-Amm, Joelle; Aragon-Ching, Jeanny B

    2015-01-01

    The vast majority of patients with metastatic castration-resistant prostate cancer (mCRPC) develop bone metastases. Bone metastases are a source of significant morbidity and affect quality of life in these patients. Several bone-targeting agents are approved for the treatment of bone metastases in prostate cancer, including bisphosphonates, denosumab, and radiopharmaceuticals. Radium-223 is a novel first-in-class alpha-emitting radiopharmaceutical that has been approved for treatment of patients with mCRPC with bone metastases. Radium-223 delivers cytotoxic radiation to the sites of bone metastases and offers the advantage of minimal myelosuppression. The landmark Phase III ALSYMPCA trial demonstrated that, in addition to providing bone-related palliation, radium-223 can also prolong overall survival in patients with mCRPC with bone metastases in the absence of visceral metastases and in the absence of lymphadenopathy greater than 3 cm. Ongoing trials will further elucidate its use in sequence or combination with other available therapies for mCRPC. PMID:26056474

  16. Cytotoxic chemotherapy in the contemporary management of metastatic castration-resistant prostate cancer (mCRPC).

    PubMed

    Sonpavde, Guru; Wang, Christopher G; Galsky, Matthew D; Oh, William K; Armstrong, Andrew J

    2015-07-01

    For several years, docetaxel was the only treatment shown to improve survival of patients with metastatic castration-resistant prostate cancer (mCRPC). There are now several novel agents available, although chemotherapy with docetaxel and cabazitaxel continues to play an important role. However, the increasing number of available agents will inevitably affect the timing of chemotherapy and therefore it may be important to offer this approach before declining performance status renders patients ineligible for chemotherapy. Patient selection is also important to optimise treatment benefit. The role of predictive biomarkers has assumed greater importance due to the development of multiple agents and resistance to available agents. In addition, the optimal sequence of treatments remains undefined and requires further study in order to maximize long-term outcomes. We provide an overview of the clinical data supporting the role of chemotherapy in the treatment of mCRPC and the emerging role in metastatic castration-sensitive prostate cancer. We review the key issues in the management of patients including selection of patients for chemotherapy, when to start chemotherapy, and how best to sequence treatments to maximise outcomes. In addition, we briefly summarise the promising new chemotherapeutic agents in development in the context of emerging therapies. PMID:25046451

  17. Inhibition of the hexosamine biosynthetic pathway promotes castration-resistant prostate cancer

    PubMed Central

    Kaushik, Akash K.; Shojaie, Ali; Panzitt, Katrin; Sonavane, Rajni; Venghatakrishnan, Harene; Manikkam, Mohan; Zaslavsky, Alexander; Putluri, Vasanta; Vasu, Vihas T.; Zhang, Yiqing; Khan, Ayesha S.; Lloyd, Stacy; Szafran, Adam T.; Dasgupta, Subhamoy; Bader, David A.; Stossi, Fabio; Li, Hangwen; Samanta, Susmita; Cao, Xuhong; Tsouko, Efrosini; Huang, Shixia; Frigo, Daniel E.; Chan, Lawrence; Edwards, Dean P.; Kaipparettu, Benny A.; Mitsiades, Nicholas; Weigel, Nancy L.; Mancini, Michael; McGuire, Sean E.; Mehra, Rohit; Ittmann, Michael M.; Chinnaiyan, Arul M.; Putluri, Nagireddy; Palapattu, Ganesh S.; Michailidis, George; Sreekumar, Arun

    2016-01-01

    The precise molecular alterations driving castration-resistant prostate cancer (CRPC) are not clearly understood. Using a novel network-based integrative approach, here, we show distinct alterations in the hexosamine biosynthetic pathway (HBP) to be critical for CRPC. Expression of HBP enzyme glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1) is found to be significantly decreased in CRPC compared with localized prostate cancer (PCa). Genetic loss-of-function of GNPNAT1 in CRPC-like cells increases proliferation and aggressiveness, in vitro and in vivo. This is mediated by either activation of the PI3K-AKT pathway in cells expressing full-length androgen receptor (AR) or by specific protein 1 (SP1)-regulated expression of carbohydrate response element-binding protein (ChREBP) in cells containing AR-V7 variant. Strikingly, addition of the HBP metabolite UDP-N-acetylglucosamine (UDP-GlcNAc) to CRPC-like cells significantly decreases cell proliferation, both in-vitro and in animal studies, while also demonstrates additive efficacy when combined with enzalutamide in-vitro. These observations demonstrate the therapeutic value of targeting HBP in CRPC. PMID:27194471

  18. Mechanistic Support for Combined MET and AR Blockade in Castration-Resistant Prostate Cancer12

    PubMed Central

    Qiao, Yuanyuan; Feng, Felix Y.; Wang, Yugang; Cao, Xuhong; Han, Sumin; Wilder-Romans, Kari; Navone, Nora M.; Logothetis, Christopher; Taichman, Russell S.; Keller, Evan T.; Palapattu, Ganesh S.; Alva, Ajjai S.; Smith, David C.; Tomlins, Scott A.; Chinnaiyan, Arul M.; Morgan, Todd M.

    2016-01-01

    A recent phase III trial of the MET kinase inhibitor cabozantinib in men with castration-resistant prostate cancer (CRPC) failed to meet its primary survival end point; however, most men with CRPC have intact androgen receptor (AR) signaling. As previous work supports negative regulation of MET by AR signaling, we hypothesized that intact AR signaling may have limited the efficacy of cabozantinib in some of these patients. To assess the role of AR signaling on MET inhibition, we first performed an in silico analysis of human CRPC tissue samples stratified by AR signaling status (+ or −), which identified MET expression as markedly increased in AR− samples. In vitro, AR signaling inhibition in AR+ CRPC models increased MET expression and resulted in susceptibility to ligand (HGF) activation. Likewise, MET inhibition was only effective in blocking cancer phenotypes in cells with MET overexpression. Using multiple AR+ CRPC in vitro and in vivo models, we showed that combined cabozantinib and enzalutamide (AR antagonist) treatment was more efficacious than either inhibitor alone. These data provide a compelling rationale to combine AR and MET inhibition in CRPC and may explain the negative results of the phase III cabozantinib study in CRPC. Similarly, the expression of MET in AR− disease, whether due to AR inhibition or loss of AR signaling, suggests potential utility for MET inhibition in select patients with AR therapy resistance and in AR− prostate cancer. PMID:26806347

  19. Inhibition of the hexosamine biosynthetic pathway promotes castration-resistant prostate cancer.

    PubMed

    Kaushik, Akash K; Shojaie, Ali; Panzitt, Katrin; Sonavane, Rajni; Venghatakrishnan, Harene; Manikkam, Mohan; Zaslavsky, Alexander; Putluri, Vasanta; Vasu, Vihas T; Zhang, Yiqing; Khan, Ayesha S; Lloyd, Stacy; Szafran, Adam T; Dasgupta, Subhamoy; Bader, David A; Stossi, Fabio; Li, Hangwen; Samanta, Susmita; Cao, Xuhong; Tsouko, Efrosini; Huang, Shixia; Frigo, Daniel E; Chan, Lawrence; Edwards, Dean P; Kaipparettu, Benny A; Mitsiades, Nicholas; Weigel, Nancy L; Mancini, Michael; McGuire, Sean E; Mehra, Rohit; Ittmann, Michael M; Chinnaiyan, Arul M; Putluri, Nagireddy; Palapattu, Ganesh S; Michailidis, George; Sreekumar, Arun

    2016-01-01

    The precise molecular alterations driving castration-resistant prostate cancer (CRPC) are not clearly understood. Using a novel network-based integrative approach, here, we show distinct alterations in the hexosamine biosynthetic pathway (HBP) to be critical for CRPC. Expression of HBP enzyme glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1) is found to be significantly decreased in CRPC compared with localized prostate cancer (PCa). Genetic loss-of-function of GNPNAT1 in CRPC-like cells increases proliferation and aggressiveness, in vitro and in vivo. This is mediated by either activation of the PI3K-AKT pathway in cells expressing full-length androgen receptor (AR) or by specific protein 1 (SP1)-regulated expression of carbohydrate response element-binding protein (ChREBP) in cells containing AR-V7 variant. Strikingly, addition of the HBP metabolite UDP-N-acetylglucosamine (UDP-GlcNAc) to CRPC-like cells significantly decreases cell proliferation, both in-vitro and in animal studies, while also demonstrates additive efficacy when combined with enzalutamide in-vitro. These observations demonstrate the therapeutic value of targeting HBP in CRPC. PMID:27194471

  20. Integrated network model provides new insights into castration-resistant prostate cancer

    PubMed Central

    Hu, Yanling; Gu, Yinmin; Wang, Huimin; Huang, Yuanjie; Zou, Yi Ming

    2015-01-01

    Castration-resistant prostate cancer (CRPC) is the main challenge for prostate cancer treatment. Recent studies have indicated that extending the treatments to simultaneously targeting different pathways could provide better approaches. To better understand the regulatory functions of different pathways, a system-wide study of CRPC regulation is necessary. For this purpose, we constructed a comprehensive CRPC regulatory network by integrating multiple pathways such as the MEK/ERK and the PI3K/AKT pathways. We studied the feedback loops of this network and found that AKT was involved in all detected negative feedback loops. We translated the network into a predictive Boolean model and analyzed the stable states and the control effects of genes using novel methods. We found that the stable states naturally divide into two obvious groups characterizing PC3 and DU145 cells respectively. Stable state analysis further revealed that several critical genes, such as PTEN, AKT, RAF, and CDKN2A, had distinct expression behaviors in different clusters. Our model predicted the control effects of many genes. We used several public datasets as well as FHL2 overexpression to verify our finding. The results of this study can help in identifying potential therapeutic targets, especially simultaneous targets of multiple pathways, for CRPC. PMID:26603105

  1. Docetaxel Rechallenge in a Heavily Pretreated Patient With Castration-Resistant Prostate Cancer

    PubMed Central

    Di Lorenzo, Giuseppe; Pagliuca, Martina; Perillo, Teresa; Benincasa, Alfonso; Bosso, Davide; De Placido, Sabino; Buonerba, Carlo

    2016-01-01

    Abstract Chemotherapy agents for patients with metastatic castration-resistant prostate cancer (mCRPC) include docetaxel and cabazitaxel. Although docetaxel is approved in the first-line treatment setting, a few studies have shown that selected patients can benefit from docetaxel rechallenge. We, here, report the case of a heavily pretreated mCRPC patient who reported clinical benefit from receiving docetaxel after previous exposure to docetaxel, cabazitaxel, abiraterone, and enzalutamide. After 4 cycles of treatment, patient's performance status had improved to 1, the hemoglobin level was 12.9 g/dL and his serum prostate specific antigen levels were reduced by >70%, with no treatment-related adverse events. Although docetaxel rechallenge is a therapeutic option for selected patients, the risk of cumulative toxicity described in literature must be carefully considered. As the risk of cabazitaxel-related cumulative toxicity is probably lower, retreatment with cabazitaxel rather than docetaxel may also be an option in the setting of heavily pretreated mCRPC patients. PMID:27057826

  2. AKR1C3 as a target in castrate resistant prostate cancer.

    PubMed

    Adeniji, Adegoke O; Chen, Mo; Penning, Trevor M

    2013-09-01

    Aberrant androgen receptor (AR) activation is the major driver of castrate resistant prostate cancer (CRPC). CRPC is ultimately fatal and more therapeutic agents are needed to treat this disease. Compounds that target the androgen axis by inhibiting androgen biosynthesis and or AR signaling are potential candidates for use in CRPC treatment and are currently being pursued aggressively. Aldo-keto reductase 1C3 (AKR1C3) plays a pivotal role in androgen biosynthesis within the prostate. It catalyzes the 17-ketoreduction of weak androgen precursors to give testosterone and 5α-dihydrotestosterone. AKR1C3 expression and activity has been implicated in the development of CRPC, making it a rational target. Selective inhibition of AKR1C3 will be important, however, due to the presence of closely related isoforms, AKR1C1 and AKR1C2 that are also involved in androgen inactivation. We examine the evidence that supports the vital role of AKR1C3 in CRPC and recent developments in the discovery of potent and selective AKR1C3 inhibitors. This article is part of a Special Issue entitled 'CSR 2013'. PMID:23748150

  3. Complete PSA Response Following Stereotactic Ablative Radiotherapy for a Bony Metastasis in the Setting of Castrate-Resistant Prostate Cancer

    PubMed Central

    Rodrigues, George

    2015-01-01

    A majority of patients with castrate-resistant prostate cancer ultimately develop distant metastases, with bone being the most common site of spread. Classically, systemic therapy has been considered the standard of care for patients with metastatic cancer. Emerging evidence, however, suggests that an intermediate oligometastatic state, between limited disease and widespread metastases, exists; theoretically, with locally ablative treatment, patients may be curable. We describe a complete PSA response following aggressive management, using stereotactic body radiotherapy (SBRT), of an oligometastatic spine lesion in the setting of castrate-resistant prostate cancer (CRPC). This case report supports the use of SBRT in oligometastatic CRPC and suggests that management of limited metastases may provide good long-term outcomes in well-selected patients. PMID:26623220

  4. Complete PSA Response Following Stereotactic Ablative Radiotherapy for a Bony Metastasis in the Setting of Castrate-Resistant Prostate Cancer.

    PubMed

    Lukovic, Jelena; Rodrigues, George

    2015-01-01

    A majority of patients with castrate-resistant prostate cancer ultimately develop distant metastases, with bone being the most common site of spread. Classically, systemic therapy has been considered the standard of care for patients with metastatic cancer. Emerging evidence, however, suggests that an intermediate oligometastatic state, between limited disease and widespread metastases, exists; theoretically, with locally ablative treatment, patients may be curable. We describe a complete PSA response following aggressive management, using stereotactic body radiotherapy (SBRT), of an oligometastatic spine lesion in the setting of castrate-resistant prostate cancer (CRPC). This case report supports the use of SBRT in oligometastatic CRPC and suggests that management of limited metastases may provide good long-term outcomes in well-selected patients. PMID:26623220

  5. Reduction in serum clusterin is a potential therapeutic biomarker in patients with castration-resistant prostate cancer treated with custirsen

    PubMed Central

    Blumenstein, Brent; Saad, Fred; Hotte, Sebastien; Chi, Kim N; Eigl, Bernhard; Gleave, Martin; Jacobs, Cindy

    2013-01-01

    Abstract Elevated levels of clusterin (CLU), a stress-induced and secreted cytoprotective chaperone, are associated with advanced tumor stage, metastasis, treatment resistance, and adverse outcome in several cancers. Custirsen, a second-generation antisense oligonucleotide, inhibits CLU production in tumor cells and reduces serum CLU levels. A Phase 2 study evaluated custirsen in combination with second-line chemotherapy in men with metastatic castration-resistant prostate cancer (mCRPC) who had progressed while on or within 6 months of first-line docetaxel-based chemotherapy. Exploratory analyses evaluated serum CLU levels during custirsen treatment and correlative clinical effects on prostate-specific antigen (PSA) response, overall survival, and any relationship between serum CLU and PSA. Men with mCRPC were treated with mitoxantrone/prednisone/custirsen (MPC, n = 22) or docetaxel retreatment/prednisone/custirsen (DPC plus DPC-Assigned, n = 45) in an open-label, multicenter study. Subject-specific profiles of PSA and serum CLU levels during treatment were characterized using statistical modeling to compute subject-specific summary measures; these measures were analyzed for relationship to survival using proportional hazard regression. Estimated individual serum CLU response profiles were scored as below or at/above the median level for the population through 100 days postrandomization. Median survival was longer for subjects scoring below the median serum CLU level compared with subjects at/above the median level, respectively (MPC: 15.1 months vs. 6.2 months; DPC-Pooled: 17.0 months vs. 12.1 months). Lowered serum CLU levels during custirsen treatment when in combination with either chemotherapy regimen were predictive of longer survival in mCRPC. These results support further evaluation of serum CLU as a therapeutic biomarker. Aside from PSA, there are currently no other prognostic or predictive biomarkers that can be used to guide treatment response

  6. LncRNA MALAT1 enhances oncogenic activities of EZH2 in castration-resistant prostate cancer

    PubMed Central

    Wang, Liguo; Zhao, Yu; Sun, Zhifu; Karnes, R. Jeffrey; Zhang, Jun; Huang, Haojie

    2015-01-01

    The Polycomb protein enhancer of zeste homolog 2 (EZH2) is frequently overexpressed in advanced human prostate cancer (PCa), especially in lethal castration-resistant prostate cancer (CRPC). However, the signaling pathways that regulate EZH2 functions in PCa remain incompletely defined. Using EZH2 antibody-based RNA immunoprecipitation-coupled high throughput sequencing (RIP-seq), we demonstrated that EZH2 binds to MALAT1, a long non-coding RNA (lncRNA) that is overexpressed during PCa progression. GST pull-down and RIP assays demonstrated that the 3′ end of MALAT1 interacts with the N-terminal of EZH2. Knockdown of MALAT1 impaired EZH2 recruitment to its target loci and upregulated expression of EZH2 repressed genes. Further studies indicated that MALAT1 plays a vital role in EZH2-enhanced migration and invasion in CRPC cell lines. Meta-analysis and RT-qPCR of patient specimens demonstrated a positive correlation between MALAT1 and EZH2 expression in human CRPC tissues. Finally, we showed that MALAT1 enhances expression of PRC2-independent target genes of EZH2 in CRPC cells in culture and patient-derived xenografts. Together, these data indicate that MALAT1 may be a crucial RNA cofactor of EZH2 and that the EZH2-MALAT1 association may provide a new avenue for development new strategies for treatment of CRPC. PMID:26516927

  7. LncRNA MALAT1 enhances oncogenic activities of EZH2 in castration-resistant prostate cancer.

    PubMed

    Wang, Dejie; Ding, Liya; Wang, Liguo; Zhao, Yu; Sun, Zhifu; Karnes, R Jeffrey; Zhang, Jun; Huang, Haojie

    2015-12-01

    The Polycomb protein enhancer of zeste homolog 2 (EZH2) is frequently overexpressed in advanced human prostate cancer (PCa), especially in lethal castration-resistant prostate cancer (CRPC). However, the signaling pathways that regulate EZH2 functions in PCa remain incompletely defined. Using EZH2 antibody-based RNA immunoprecipitation-coupled high throughput sequencing (RIP-seq), we demonstrated that EZH2 binds to MALAT1, a long non-coding RNA (lncRNA) that is overexpressed during PCa progression. GST pull-down and RIP assays demonstrated that the 3' end of MALAT1 interacts with the N-terminal of EZH2. Knockdown of MALAT1 impaired EZH2 recruitment to its target loci and upregulated expression of EZH2 repressed genes. Further studies indicated that MALAT1 plays a vital role in EZH2-enhanced migration and invasion in CRPC cell lines. Meta-analysis and RT-qPCR of patient specimens demonstrated a positive correlation between MALAT1 and EZH2 expression in human CRPC tissues. Finally, we showed that MALAT1 enhances expression of PRC2-independent target genes of EZH2 in CRPC cells in culture and patient-derived xenografts. Together, these data indicate that MALAT1 may be a crucial RNA cofactor of EZH2 and that the EZH2-MALAT1 association may provide a new avenue for development new strategies for treatment of CRPC. PMID:26516927

  8. Development of AR-V7 as a putative treatment selection marker for metastatic castration-resistant prostate cancer

    PubMed Central

    Luo, Jun

    2016-01-01

    Prostate cancer cells demonstrate a remarkable “addiction” to androgen receptor (AR) signaling in all stages of disease progression. As such, suppression of AR signaling remains the therapeutic goal in systemic treatment of prostate cancer. A number of molecular alterations arise in patients treated with AR-directed therapies. These molecular alterations may indicate the emergence of treatment resistance and may be targeted for the development of novel agents for prostate cancer. The presence of functional androgen receptor splice variants may represent a potential explanation for resistance to abiraterone and enzalutamide, newer AR-directed agents developed to treat metastatic castration-resistant prostate cancer (mCRPC). In the last 8 years, many androgen receptor splice variants have been identified and characterized. Among these, androgen receptor splice variant-7 (AR-V7) has been investigated extensively. In AR-V7, the entire COOH-terminal ligand-binding domain of the canonical AR is truncated and replaced with a variant-specific peptide of 16 amino acids. Functionally, AR-V7 is capable of mediating constitutive nuclear localization and androgen receptor signaling in the absence of androgens, or in the presence of enzalutamide. In this review, we will focus on clinical translational studies involving detection/measurement of AR-V7. Methods have been developed to detect AR-V7 in clinical mCRPC specimens. AR-V7 can be reliably measured in both tissue and circulating tumor cells derived from mCRPC patients, making it possible to conduct both cross-sectional and longitudinal clinical correlative studies. Current evidence derived from studies focusing on detection of AR-V7 in mCRPC support its potential clinical utility as a treatment selection marker. PMID:27174161

  9. Low-dose docetaxel, estramustine and prednisolone combination chemotherapy for castration-resistant prostate cancer

    PubMed Central

    NAKANO, MAYURA; SHOJI, SUNAO; HIGURE, TARO; KAWAKAMI, MASAYOSHI; TOMONAGA, TETSURO; TERACHI, TOSHIRO; UCHIDA, TOYOAKI

    2016-01-01

    The objective of this study was to report our experience with weekly low-dose docetaxel (DOC) chemotherapy for patients with castration-resistant prostate cancer (CRPC). From 2007 to 2014, 39 consecutive patients received weekly low-dose DOC; the oncological effectiveness, side effects and tolerability were prospectively analyzed. The median patient age, serum prostate-specific antigen (PSA) level and Gleason score at diagnosis of prostate cancer were 71 years (range, 55–83 years), 187 ng/ml (range, 2.0–1711 ng/ml) and 8 (range, 5–10), respectively. The median number of cycles of DOC was 7 (range, 1–45 cycles). Of the 39 patients, the PSA level decreased by >50% in 13 (33%). In the multivariate analysis of prediction of patient overall survival, a decrease of the PSA level to <50% was a significant predictor (hazard ratio = 6.913; 95% confidence interval: 1.147–41.669; P=0.035). The median cancer-specific overall survival from the diagnosis of CRPC was 16.7 months (range, 2–54 months). Grade 3 toxicities were observed in 5 patients (13%); specifically, limb edema, nausea and hepatic disorders were detected in 2 (5%), 2 (5%) and 1 patient (3%), respectively. Treatment-related death (grade 5) occurred in 1 patient due to interstitial pneumonia after two courses of chemotherapy. The chemotherapy was completed in the majority of the patients (n=37, 94.8%) in the outpatient department, without interruption. These findings suggest that weekly low-dose DOC is feasible and safe for selected patients with CRPC, without treament with novel agents, such as abiraterone, enzalutamide and cabazitaxel. PMID:27284427

  10. Cryptotanshinone Suppresses Androgen Receptor-mediated Growth in Androgen Dependent and Castration Resistant Prostate Cancer Cells

    PubMed Central

    Xu, Defeng; Lin, Tzu-Hua; Li, Shaoshun; Da, Jun; Wen, Xing-Qiao; Ding, Jiang; Chang, Chawnshang; Yeh, Shuyuan

    2012-01-01

    Androgen receptor (AR) is the major therapeutic target for the treatment of prostate cancer (PCa). Anti-androgens to reduce or prevent androgens binding to AR are widely used to suppress AR-mediated PCa growth; however, the androgen depletion therapy is only effective for a period of time. Here we found a natural product/Chinese herbal medicine cryptotanshinone (CTS), with a structure similar to dihydrotestosterone (DHT), can effectively inhibit the DHT-induced AR transactivation and prostate cancer cell growth. Our results indicated that 0.5 µM CTS effectively suppresses the growth of AR-positive PCa cells, but has little effect on AR negative PC-3 cells and non-malignant prostate epithelial cells. Furthermore, our data indicated that CTS could modulate AR transactivation and suppress the DHT-mediated AR target genes (PSA, TMPRSS2, and TMEPA1) expression in both androgen responsive PCa LNCaP cells and castration resistant CWR22rv1 cells. Importantly, CTS selective inhibits AR without repressing the activities of other nuclear receptors, including ERα, GR, and PR. The mechanistic studies indicate that CTS functions as an AR inhibitor to suppress androgen/AR-mediated cell growth and PSA expression by blocking AR dimerization and the AR–coregulator complex formation. Furthermore, we showed that CTS effectively inhibits CWR22Rv1 cell growth in the xenograft animal model. The previously un-described mechanisms of CTS may explain how CTS inhibits the growth of PCa cells and help us to establish new therapeutic concepts for the treatment of PCa. PMID:22154085

  11. Human castration resistant prostate cancer rather prefer to decreased 5α-reductase activity

    PubMed Central

    Kosaka, Takeo; Miyajima, Akira; Nagata, Hirohiko; Maeda, Takahiro; Kikuchi, Eiji; Oya, Mototsugu

    2013-01-01

    Physiologically relevant steroid 5α-reductase (SRD5A) activity that is essential for dihydrotestosterone (DHT) biosynthesis in human castration-resistant prostate cancer (CRPC) has not been fully characterized yet. In this study to ascertain the potential SRD5A activity, we cultured two human CRPC cell lines, C4-2 and C4-2AT6, with the steroid precursor: 13C-[2,3,4]-androstenedione (13C-Adione), and analyzed the sequential biosynthesis of 13C-[2,3,4]-testosterone (13C-T) and 13C-[2,3,4]-DHT (13C-DHT) by liquid chromatography/mass spectrometry (LC/MS/MS). The 13C-DHT/13C-T concentration ratio detected by LC/MS/MS in C4-2AT6 cells appeared to reflect the SRD5A activity. The ratio in C4-2AT6 was significantly lower than that in C4-2. An increased concentration of DHT did not have a positive effect on cell proliferation, rather it exhibited inhibitory effects. 5α-reductase inhibitors did not have any inhibitory effect at clinically achievable concentrations. These results indicate that CRPC cells may have an unknown regulation system to protect themselves from an androgenic suppressive effect mediated by SRD5A activity. PMID:23429215

  12. [Metastatic castration-resistant prostate cancer : Clinical data, new treatment options and therapy monitoring].

    PubMed

    Miller, K; Albers, P; Eichenauer, R; Geiges, G; Grimm, M-O; König, F; Mickisch, G; Pfister, D; Schwentner, C; Suttmann, H; Zastrow, S

    2016-09-01

    Therapies currently available in Germany for metastatic castration-resistant prostate cancer (mCRPC) include docetaxel, cabazitaxel, abiraterone acetate, enzalutamide and radium-223, all of which offer a potential survival benefit that adds up in their sequential application to a significant overall survival benefit. However, the optimal sequencing of these agents is still unclear. In the absence of evidence, treatment selection is based on the particular situation and on comorbid conditions of each individual patient. Furthermore, predictive markers to facilitate the selection of patients for a specific therapy or sequence of therapies remain an unmet need. However, with the recently discovered androgen receptor splice variant V7, which mediates (cross)resistance to or between abiraterone and enzalutamide, the first such marker has been identified. It is critical to monitor the response to treatments at prespecified intervals in order to optimize treatment sequencing so that the patient does not miss a valuable therapeutic window to receive alternative treatment that may prolong his life along with good symptom control and preservation of quality of life. PMID:27411995

  13. Resistance to Novel Antiandrogen Therapies in Metastatic Castration-Resistant Prostate Cancer

    PubMed Central

    Boudadi, Karim; Antonarakis, Emmanuel S.

    2016-01-01

    Despite the introduction of novel therapies that maximally decrease androgen-receptor (AR) signaling activity, metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease. Even though abiraterone and enzalutamide represent breakthroughs in the treatment of mCRPC and have demonstrated significant survival benefits, a significant proportion of patients have primary resistance to these agents and virtually all patients develop secondary resistance. While the mechanisms of resistance to these agents are not fully understood, many hypotheses of AR-dependent and AR-independent mechanisms are emerging, including upregulation of AR and cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17), induction of AR splice variants, AR point mutations, upregulation of glucocorticoid receptor, activation of alternative oncogenic signaling pathways, neuroendocrine transformation, and immune evasion via programmed death-ligand 1 upregulation. The aim of this review is to summarize the most clinically relevant mechanisms of resistance to novel androgen-directed agents, focusing on escape from enzalutamide and abiraterone. PMID:27013902

  14. A combination of sorafenib and nilotinib reduces the growth of castrate-resistant prostate cancer

    PubMed Central

    Archibald, Monica; Pritchard, Tara; Nehoff, Hayley; Rosengren, Rhonda J; Greish, Khaled; Taurin, Sebastien

    2016-01-01

    Castrate-resistant prostate cancer (CRPC) remains incurable due to the lack of effective therapies. Several tyrosine kinases have been implicated in the development and growth of CRPC, as such targeting these kinases may offer an alternative therapeutic strategy. We established the combination of two tyrosine kinase inhibitors (TKIs), sorafenib and nilotinib, as the most cytotoxic. In addtion, to improve their bioavailability and reduce their metabolism, we encapsulated sorafenib and nilotinib into styrene-co-maleic acid micelles. The micelles’ charge, size, and release rate were characterized. We assessed the effect of the combination on the cytotoxicity, cell cycle, apoptosis, protein expression, tumor spheroid integrity, migration, and invasion. The micelles exhibited a mean diameter of 100 nm, a neutral charge, and appeared highly stable. The micellar TKIs promoted greater cytotoxicity, decreased cell proliferation, and increased apoptosis relative to the free TKIs. In addition, the combination reduced the expression and activity of several tyrosine kinases and reduced tumor spheroid integrity and metastatic potential of CRPC cell lines more efficiently than the single treatments. The combination increased the therapeutic potential and demonstrated the relevance of a targeted combination therapy for the treatment of CRPC. In addition, the efficacy of the encapsulated drugs provides the basis for an in vivo preclinical testing. PMID:26811677

  15. A combination of sorafenib and nilotinib reduces the growth of castrate-resistant prostate cancer.

    PubMed

    Archibald, Monica; Pritchard, Tara; Nehoff, Hayley; Rosengren, Rhonda J; Greish, Khaled; Taurin, Sebastien

    2016-01-01

    Castrate-resistant prostate cancer (CRPC) remains incurable due to the lack of effective therapies. Several tyrosine kinases have been implicated in the development and growth of CRPC, as such targeting these kinases may offer an alternative therapeutic strategy. We established the combination of two tyrosine kinase inhibitors (TKIs), sorafenib and nilotinib, as the most cytotoxic. In addtion, to improve their bioavailability and reduce their metabolism, we encapsulated sorafenib and nilotinib into styrene-co-maleic acid micelles. The micelles' charge, size, and release rate were characterized. We assessed the effect of the combination on the cytotoxicity, cell cycle, apoptosis, protein expression, tumor spheroid integrity, migration, and invasion. The micelles exhibited a mean diameter of 100 nm, a neutral charge, and appeared highly stable. The micellar TKIs promoted greater cytotoxicity, decreased cell proliferation, and increased apoptosis relative to the free TKIs. In addition, the combination reduced the expression and activity of several tyrosine kinases and reduced tumor spheroid integrity and metastatic potential of CRPC cell lines more efficiently than the single treatments. The combination increased the therapeutic potential and demonstrated the relevance of a targeted combination therapy for the treatment of CRPC. In addition, the efficacy of the encapsulated drugs provides the basis for an in vivo preclinical testing. PMID:26811677

  16. Metastatic castration-resistant prostate cancer: new therapies, novel combination strategies and implications for immunotherapy

    PubMed Central

    Drake, CG; Sharma, P; Gerritsen, W

    2016-01-01

    For the past decade, docetaxel has remained the global standard of care for frontline treatment of metastatic castration-resistant prostate cancer (mCRPC). Until recently, there were limited options for patients with mCRPC following docetaxel failure or resistance, but now the approved treatment choices for these patients have expanded to include abiraterone acetate, cabazitaxel and enzalutamide. Additionally, the radioactive therapeutic agent radium-223 dichloride has been recently approved in patients with CRPC with bone metastases. Although each of these agents has been shown to convey significant survival benefit as a monotherapy, preclinical findings suggest that combining such innovative strategies with traditional treatments may achieve additive or synergistic effects, further augmenting patient benefit. This review will discuss the transformation of the post-docetaxel space in mCRPC, highlighting the spectrum of newly approved agents in this setting in the USA and the European Union, as well as summarizing treatments with non-chemotherapeutic mechanisms of action that have demonstrated promising results in recent phase 3 trials. Lastly, this review will address the potential of combinatorial regimens in mCRPC, including the pairing of novel immunotherapeutic approaches with chemotherapy, radiotherapy or androgen ablation. PMID:24276248

  17. A phase II trial of dasatinib in patients with metastatic castration-resistant prostate cancer treated previously with chemotherapy

    PubMed Central

    Twardowski, Przemyslaw W.; Beumer, Jan H.; Chen, C.S.; Kraft, Andrew S.; Chatta, Gurkamal S.; Mitsuhashi, Masato; Ye, Wei; Christner, Susan M.; Lilly, Michael B.

    2014-01-01

    There is a need for efficacious therapies for metastatic castration-resistant prostate cancer (mCRPC) after disease progression on docetaxel. The SRC tyrosine kinase and its related family members may be important drivers of prostate cancer and can be inhibited by dasatinib. mCRPC patients, after one previous chemotherapy, started dasatinib at 70mg twice daily, amended to 100mg daily. The primary endpoint was the disease control (DC) rate, defined as complete response (CR), partial response (PR), or stable disease (SD) in prostate specific antigen (PSA), RECIST, bone scan, and FACT-P score. Up to 41 patients were to be accrued (two-stage design, 21+20) to rule out a null-hypothesized effect of 5 versus 20% (α=0.05, β=0.1). Secondary endpoints included progression-free survival, toxicity, and pharmacokinetic and pharmacodynamic correlatives. Of 38 patients, 27 were evaluable for response or toxicity. The median duration of therapy was 55 days (6–284). Five patients showed DC after 8 weeks of therapy (18.5% DC, 95% CI: 6.3–38.1%). One PR (3.7% response rate, 95% CI: 0.1–19.0%) was observed in a patient treated for 284 days. Twelve patients (43%) discontinued treatment for toxicity. Dasatinib induced a decrease in phytohemagglutinin-stimulated CSF2, CD40L, GZMB, and IL-2 mRNAs in blood cells, indicating target engagement. Decreases in plasma IL-6 and bone alkaline phosphatase, and in urinary N-telopeptide, were associated with DC. Dasatinib has definite but limited activity in advanced mCRPC, and was poorly tolerated. The observation of a patient with prolonged, objective, clinically significant benefit warrants molecular profiling to select the appropriate patient population. PMID:23652277

  18. A phase II trial of dasatinib in patients with metastatic castration-resistant prostate cancer treated previously with chemotherapy.

    PubMed

    Twardowski, Przemyslaw W; Beumer, Jan H; Chen, C S; Kraft, Andrew S; Chatta, Gurkamal S; Mitsuhashi, Masato; Ye, Wei; Christner, Susan M; Lilly, Michael B

    2013-08-01

    There is a need for efficacious therapies for metastatic castration-resistant prostate cancer (mCRPC) after disease progression on docetaxel. The SRC tyrosine kinase and its related family members may be important drivers of prostate cancer and can be inhibited by dasatinib. mCRPC patients, after one previous chemotherapy, started dasatinib at 70 mg twice daily, amended to 100 mg daily. The primary endpoint was the disease control (DC) rate, defined as complete response (CR), partial response (PR), or stable disease (SD) in prostate specific antigen (PSA), RECIST, bone scan, and FACT-P score. Up to 41 patients were to be accrued (two-stage design, 21+20) to rule out a null-hypothesized effect of 5 versus 20% (α=0.05, β=0.1). Secondary endpoints included progression-free survival, toxicity, and pharmacokinetic and pharmacodynamic correlatives. Of 38 patients, 27 were evaluable for response or toxicity. The median duration of therapy was 55 days (6-284). Five patients showed DC after 8 weeks of therapy (18.5% DC, 95% CI: 6.3-38.1%). One PR (3.7% response rate, 95% CI: 0.1-19.0%) was observed in a patient treated for 284 days. Twelve patients (43%) discontinued treatment for toxicity. Dasatinib induced a decrease in phytohemagglutinin-stimulated CSF2, CD40L, GZMB, and IL-2 mRNAs in blood cells, indicating target engagement. Decreases in plasma IL-6 and bone alkaline phosphatase, and in urinary N-telopeptide, were associated with DC. Dasatinib has definite but limited activity in advanced mCRPC, and was poorly tolerated. The observation of a patient with prolonged, objective, clinically significant benefit warrants molecular profiling to select the appropriate patient population. PMID:23652277

  19. Downregulation of c-SRC kinase CSK promotes castration resistant prostate cancer and pinpoints a novel disease subclass.

    PubMed

    Yang, Chih-Cheng; Fazli, Ladan; Loguercio, Salvatore; Zharkikh, Irina; Aza-Blanc, Pedro; Gleave, Martin E; Wolf, Dieter A

    2015-09-01

    SRC kinase is activated in castration resistant prostate cancer (CRPC), phosphorylates the androgen receptor (AR), and causes its ligand-independent activation as a transcription factor. However, activating SRC mutations are exceedingly rare in human tumors, and mechanisms of ectopic SRC activation therefore remain largely unknown. Performing a functional genomics screen, we found that downregulation of SRC inhibitory kinase CSK is sufficient to overcome growth arrest induced by depriving human prostate cancer cells of androgen. CSK knockdown led to ectopic SRC activation, increased AR signaling, and resistance to anti-androgens. Consistent with the in vitro observations, stable knockdown of CSK conferred castration resistance in mouse xenograft models, while sensitivity to the tyrosine kinase inhibitor dasatinib was retained. Finally, CSK was found downregulated in a distinct subset of CRPCs marked by AR amplification and ETS2 deletion but lacking PTEN and RB1 mutations. These results identify CSK downregulation as a principal driver of SRC activation and castration resistance and validate SRC as a drug target in a molecularly defined subclass of CRPCs. PMID:26091350

  20. PTEN Protein Loss and Clinical Outcome from Castration-resistant Prostate Cancer Treated with Abiraterone Acetate

    PubMed Central

    Ferraldeschi, Roberta; Nava Rodrigues, Daniel; Riisnaes, Ruth; Miranda, Susana; Figueiredo, Ines; Rescigno, Pasquale; Ravi, Praful; Pezaro, Carmel; Omlin, Aurelius; Lorente, David; Zafeiriou, Zafeiris; Mateo, Joaquin; Altavilla, Amelia; Sideris, Spyridon; Bianchini, Diletta; Grist, Emily; Thway, Khin; Perez Lopez, Raquel; Tunariu, Nina; Parker, Chris; Dearnaley, David; Reid, Alison; Attard, Gerhardt; de Bono, Johann

    2015-01-01

    Background Loss of the tumor suppressor phosphatase and tensin homolog (PTEN) occurs frequently in prostate cancers. Preclinical evidence suggests that activation of PI3K/AKT signaling through loss of PTEN can result in resistance to hormonal treatment in prostate cancer. Objective To explore the antitumor activity of abiraterone acetate (abiraterone) in castration-resistant prostate cancer (CRPC) patients with and without loss of PTEN protein expression. Design, setting, and participants We retrospectively identified patients who had received abiraterone and had hormone-sensitive prostate cancer (HSPC) and/or CRPC tissue available for PTEN immunohistochemical analysis. Outcome measurements and statistical analysis The primary end point was overall survival from initiation of abiraterone treatment. Relationship with outcome was analyzed using multivariate Cox regression and log-rank analyses. Results and limitations A total of 144 patients were identified who had received abiraterone post-docetaxel and had available tumor tissue. Overall, loss of PTEN expression was observed in 40% of patients. Matched HSPC and CRPC tumor biopsies were available for 41 patients. PTEN status in CRPC correlated with HSPC in 86% of cases. Loss of PTEN expression was associated with shorter median overall survival (14 vs 21 mo; hazard ratio [HR]: 1.75; 95% confidence interval [CI], 1.19–2.55; p = 0.004) and shorter median duration of abiraterone treatment (24 vs 28 wk; HR: 1.6; 95% CI, 1.12–2.28; p = 0.009). PTEN protein loss, high lactate dehydrogenase, and the presence of visceral metastases were identified as independent prognostic factors in multivariate analysis. Conclusions Our results indicate that loss of PTEN expression was associated with worse survival and shorter time on abiraterone treatment. Further studies in larger and prospective cohorts are warranted. Patient summary PTEN is a protein often lost in prostate cancer cells. In this study we evaluated if prostate

  1. Challenges in generating costs and utilisation rates associated with castration-resistant prostate cancer

    PubMed Central

    Bourke, Siobhan; Burns, Richéal Maria; Gaynor, Caroline

    2014-01-01

    Background Prostate cancer (PCa), the most commonly diagnosed cancer among men in the United States and Europe, is an escalating resource allocation issue across healthcare systems in the Western world. The impact of skeletal-related events, associated with castration-resistant prostate cancer (CRPC), is considerable with many new therapies being sought to treat these events in a cost-effective manner. Aims The aim of this paper is to provide insight into the level of constraints associated with devising cost frameworks for economic analysis of CRPC in the Irish healthcare setting. Methods An informal questionnaire was devised to obtain estimates of utilisation to populate a decision tree model; existing parameters from the literature were also employed. Cost parameters included Irish reference costs, and a costs literature review was undertaken; a healthcare payer perspective was adopted. Pharmacy dosages used for modelling costs were calculated for an average 75 kg male. Results The estimated average cost of care associated with adverse events in CRPC was €23,264. Approximately 40% of the costs of CRPC are attributed to skeletal-related events; therefore, reducing the number of skeletal-related events could significantly reduce the cost of care. In attempting to generate accurate and reliable cost parameters, this study highlights the challenges of conducting economic analysis in the Irish healthcare setting. Conclusion This study presents leading treatments and associated costs for CRPC patients in the Republic of Ireland (RoI), which are expected to steadily increase with demographic shifts. Further research is warranted in this area due to the limitations encountered in the study.

  2. Androgen synthesis inhibitors in the treatment of castration-resistant prostate cancer

    PubMed Central

    Stein, Mark N; Patel, Neal; Bershadskiy, Alexander; Sokoloff, Alisa; Singer, Eric A

    2014-01-01

    Suppression of gonadal testosterone synthesis represents the standard first line therapy for treatment of metastatic prostate cancer. However, in the majority of patients who develop castration-resistant prostate cancer (CRPC), it is possible to detect persistent activation of the androgen receptor (AR) through androgens produced in the adrenal gland or within the tumor itself. Abiraterone acetate was developed as an irreversible inhibitor of the dual functional cytochrome P450 enzyme CYP17 with activity as a 17α-hydroxylase and 17,20-lyase. CYP17 is necessary for production of nongonadal androgens from cholesterol. Regulatory approval of abiraterone in 2011, based on a phase III trial showing a significant improvement in overall survival (OS) with abiraterone and prednisone versus prednisone, represented proof of principle that targeting AR is essential for improving outcomes in men with CRPC. Inhibition of 17α-hydroxylase by abiraterone results in accumulation of upstream mineralocorticoids due to loss of cortisol-mediated suppression of pituitary adrenocorticotropic hormone (ACTH), providing a rationale for development of CYP17 inhibitors with increased specificity for 17,20-lyase (orteronel, galeterone and VT-464) that can potentially be administered without exogenous corticosteroids. In this article, we review the development of abiraterone and other CYP17 inhibitors; recent studies with abiraterone that inform our understanding of clinical parameters such as drug effects on quality-of-life, potential early predictors of response, and optimal sequencing of abiraterone with respect to other agents; and results of translational studies providing insights into resistance mechanisms to CYP17 inhibitors leading to clinical trials with drug combinations designed to prolong abiraterone benefit or restore abiraterone activity. PMID:24759590

  3. Patient experience in the treatment of metastatic castration-resistant prostate cancer: state of the science

    PubMed Central

    Nussbaum, N; George, D J; Abernethy, A P; Dolan, C M; Oestreicher, N; Flanders, S; Dorff, T B

    2016-01-01

    Background: Contemporary therapies for metastatic castration-resistant prostate cancer (mCRPC) have shown survival improvements, which do not account for patient experience and health-related quality of life (HRQoL). Methods: This literature review included a search of MEDLINE for randomized clinical trials enrolling ⩾50 patients with mCRPC and reporting on patient-reported outcomes (PROs) since 2010. Results: Nineteen of 25 publications describing seven treatment regimens (10 clinical trials and nine associated secondary analyses) met the inclusion criteria and were critically appraised. The most commonly used measures were the Functional Assessment of Cancer Therapy-Prostate (n=5 trials) and Brief Pain Inventory Short Form (n=4 trials) questionnaires. The published data indicated that HRQoL and pain status augmented the clinical efficacy data by providing a better understanding of treatment impact in mCRPC. Abiraterone acetate and prednisone, enzalutamide, radium-223 dichloride and sipuleucel-T offered varying levels of HRQoL benefit and/or pain mitigation versus their respective comparators, whereas three treatments (mitoxantrone, estramustine phosphate and docetaxel, and cabazitaxel) had no meaningful impact on HRQoL or pain. The main limitation of the data were that the PROs utilized were not developed for use in mCRPC patients and hence may not have comprehensively captured symptoms important to this population. Conclusions: Recently published randomized clinical trials of new agents for mCRPC have captured elements of the patient experience while on treatment. Further research is required to standardize methods for measuring, quantifying and reporting on HRQoL and pain in patients with mCRPC in the clinical practice setting. PMID:26832363

  4. Treatment of castration-resistant prostate cancer and bone metastases with radium-223 dichloride

    PubMed Central

    Lien, Lise Marie E; Tvedt, Birger; Heinrich, Daniel

    2015-01-01

    Radium-223 dichloride (Ra-223) is the first α-particle emitting radiopharmaceutical to be approved for the treatment of patients with castration-resistant prostate cancer and associated bone metastases, and the first bone-targeting agent to significantly improve patient overall survival whilst reducing pain and the symptomatic skeletal events (SSEs) associated with bone metastases. Ra-223 exhibits a favourable safety profile, with low myelosuppression rates and fewer adverse events than placebo. Compared with other approved radiopharmaceuticals, the α-particle emitting Ra-223 has a high biological efficiency and a short penetration range, potentially sparing bone marrow toxicity and limiting unwanted exposure. Ra-223 has a short half-life and decays to a stable product, reducing the problem of storage and disposal associated with radiopharmaceuticals. Ra-223 offers a new treatment option with great potential in this setting. However, concerns remain amongst patients, their families and health care professionals over the use of radiopharmaceuticals. This article, which draws on the experiences of health care workers during the ALSYMPCA (ALpharadin in SYMtomatic Prostate CAncer) study, reviews the clinical development of Ra-223, highlighting the key issues for the uro-oncology nurse who has a pivotal role within the multi-disciplinary team (MDT) to ensure safe and effective treatment to the patient. The role of the uro-oncology nurse is multifaceted, including patient pre-assessment and post-treatment monitoring and coordination of the MDT. In addition, their role in communicating with and educating those involved with Ra-223 on what to expect from the agent can alleviate fears associated with its use. PMID:26097500

  5. External validation of risk classification in patients with docetaxel-treated castration-resistant prostate cancer

    PubMed Central

    2014-01-01

    Background Castration-resistant prostate cancer (CRPC) patients have poor prognoses, and docetaxel (DTX) is among the few treatment options. An accurate risk classification to identify CRPC patient groups for which DTX would be effective is urgently warranted. The Armstrong risk classification (ARC), which classifies CRPC patients into 3 groups, is superior; however, its usefulness remains unclear, and further external validation is required before clinical use. This study aimed to examine the clinical significance of the ARC through external validation in DTX-treated Japanese CRPC patients. Methods CRPC patients who received 2 or more DTX cycles were selected for this study. Patients were classified into good-, intermediate-, and poor-risk groups according to the ARC. Prostate-specific antigen (PSA) responses and overall survival (OS) were calculated and compared between the risk groups. A multivariate analysis was performed to clarify the relationship between the ARC and major patient characteristics. Results Seventy-eight CRPC patients met the inclusion criteria. Median PSA levels at DTX initiation was 20 ng/mL. Good-, intermediate-, and poor-risk groups comprised 51 (65%), 17 (22%), and 10 (13%) patients, respectively. PSA response rates ≥30% and ≥50% were 33%, 41%, and 30%, and 18%, 41%, and 20% in the good-, intermediate-, and poor-risk groups, respectivcixely, with no significant differences (p = 0.133 and 0.797, respectively). The median OS in the good-, intermediate-, and poor-risk groups were statistically significant (p < 0.001) at 30.1, 14.2, and 5.7 months, respectively. A multivariate analysis revealed that the ARC and PSA doubling time were independent prognostic factors. Conclusions Most of CRPC patients were classified into good-risk group according to the ARC and the ARC could predict prognosis in DTX-treated CRPC patients. Trial registration University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) number

  6. Activation of P-TEFb by Androgen Receptor-Regulated Enhancer RNAs in Castration-Resistant Prostate Cancer.

    PubMed

    Zhao, Yu; Wang, Liguo; Ren, Shancheng; Wang, Lan; Blackburn, Patrick R; McNulty, Melissa S; Gao, Xu; Qiao, Meng; Vessella, Robert L; Kohli, Manish; Zhang, Jun; Karnes, R Jeffrey; Tindall, Donald J; Kim, Youngsoo; MacLeod, Robert; Ekker, Stephen C; Kang, Tiebang; Sun, Yinghao; Huang, Haojie

    2016-04-19

    The androgen receptor (AR) is required for castration-resistant prostate cancer (CRPC) progression, but the function and disease relevance of AR-bound enhancers remain unclear. Here, we identify a group of AR-regulated enhancer RNAs (e.g., PSA eRNA) that are upregulated in CRPC cells, patient-derived xenografts (PDXs), and patient tissues. PSA eRNA binds to CYCLIN T1, activates P-TEFb, and promotes cis and trans target gene transcription by increasing serine-2 phosphorylation of RNA polymerase II (Pol II-Ser2p). We define an HIV-1 TAR RNA-like (TAR-L) motif in PSA eRNA that is required for CYCLIN T1 binding. Using TALEN-mediated gene editing we further demonstrate that this motif is essential for increased Pol II-Ser2p occupancy levels and CRPC cell growth. We have uncovered a P-TEFb activation mechanism and reveal altered eRNA expression that is related to abnormal AR function and may potentially be a therapeutic target in CRPC. PMID:27068475

  7. Integrating bone targeting radiopharmaceuticals into the management of patients with castrate-resistant prostate cancer with symptomatic bone metastases.

    PubMed

    Blacksburg, Seth R; Witten, Matthew R; Haas, Jonathan A

    2015-03-01

    Metastatic castrate-resistant prostate cancer (CRPC) refers to the disease state in which metastatic prostate cancer fails to respond to androgen deprivation therapy (ADT). This can be manifest as a rising PSA, increase in radiographically measurable disease, or progression of clinical disease. Roughly 90 % of men with metastatic prostate cancer have bone metastases, which is a predictor of both morbidity and mortality. Historically, treatment has been palliative, consisting of external beam radiation therapy (EBRT) and pharmacological analgesics for pain control and osteoclast inhibitors, such as bisphosphonates and denosumab to mitigate skeletal-related events. Older radiopharmaceuticals, such as Strontium-89 and Samarium-153, are Beta-emitting agents that were found to provide palliation but were without survival benefit and carried high risks of myelosuppression. Radium-223 is an Alpha-emitting radiopharmaceutical that has demonstrated a significant overall survival benefit in men with metastatic CRPC, delay to symptomatic skeletal events (SSEs), and improvement in pain control, with a favorable toxicity profile compared with placebo. Unlike EBRT, Radium-223 has systemic uptake, with the potential to address several bone metastases concurrently and provides overall survival benefit. It is a simple administration with minimal complexity and shielding requirements in experienced hands. EBRT appears to provide a more rapid and dramatic palliative benefit to any given lesion. Because Radium-223 has limited myelosuppression, the two can be thoughtfully integrated, along with multiple agents, for the treatment of men with CRPC with symptomatic bone metastases. Given its excellent safety profile, there is interest and anecdotal safety combining Radium-223 with therapies, such as abiraterone and enzalutamide. Formal recommendations regarding combination therapies will require clinical trials. The use of Alpha-emitting radiopharmaceuticals in castrate-sensitive disease

  8. Early Prediction of Therapy Response to Abiraterone Acetate Using PSA Subforms in Patients with Castration Resistant Prostate Cancer.

    PubMed

    Schlack, Katrin; Krabbe, Laura-Maria; Fobker, Manfred; Schrader, Andres Jan; Semjonow, Axel; Boegemann, Martin

    2016-01-01

    The purpose of this study was to evaluate the prognostic ability of early changes of total prostate specific antigen (tPSA), free PSA (fPSA), [-2]proPSA and the Prostate Health Index (PHI) following initiation of Abiraterone-therapy in men with castration resistant prostate cancer (mCRPC). In 25 patients, PSA-subforms were analyzed before and at 8-12 weeks under therapy as prognosticators of progression-free-survival (PFS) and overall survival (OS). Comparing patients with a PFS < vs. ≥12 months by using Mann-Whitney-Wilcoxon Tests, the relative-median-change of tPSA (-0.1% vs. -86.8%; p = 0.02), fPSA (12.1% vs. -55.3%; p = 0.03) and [-2]proPSA (8.1% vs. -59.3%; p = 0.05) differed significantly. For men with ≤ vs. >15 months of OS there was a non-significant trend for a difference in the relative-median-change of fPSA (17.0% vs. -46.3%; p = 0.06). In Kaplan-Meier analyses, declining fPSA and [-2]proPSA were associated with a longer median PFS (13 months, 95% confidence interval (CI): 9.6-16.4 vs. 10 months, 95% CI: 3.5-16.5; p = 0.11), respectively. Correspondingly, decreasing fPSA and [-2]proPSA values indicated an OS of 32 months (95% CI: not reached (NR)) compared to 21 months in men with rising values (95% CI: 7.7-34.3; p = 0.14), respectively. We concluded that the addition of fPSA- and [-2]proPSA-changes to tPSA-information might be further studied as potential markers of early Abiraterone response in mCRPC patients. PMID:27618028

  9. Effect of bipolar androgen therapy for asymptomatic men with castration-resistant prostate cancer: Results from a pilot clinical study

    PubMed Central

    Schweizer, Michael T.; Antonarakis, Emmanuel S.; Wang, Hao; Ajiboye, A. Seun; Spitz, Avery; Cao, Haiyi; Luo, Jun; Haffner, Michael C.; Yegnasubramanian, Srinivasan; Carducci, Michael A.; Eisenberger, Mario A.; Isaacs, John T.; Denmeade, Samuel R.

    2015-01-01

    Targeting androgen receptor (AR) axis signaling by disrupting androgen-AR interactions remains the primary treatment for metastatic prostate cancer. Unfortunately, all men develop resistance to primary castrating therapy and secondary androgen deprivation therapies (ADTs). Resistance develops in part because castration-resistant prostate cancer (CRPC) cells adaptively up-regulate AR levels through overexpression, amplification, and expression of ligand-independent variants in response to chronic exposure to a low-testosterone environment. However, preclinical models suggest that AR overexpression represents a therapeutic liability that can be exploited via exposure to supraphysiologic testosterone to promote CRPC cell death. Preclinical data supported a pilot study in which 16 asymptomatic CRPC patients with low to moderate metastatic burden were treated with testosterone cypionate (400 mg intramuscular; day 1 of 28) and etoposide (100 mg oral daily; days 1 to 14 of 28). After three cycles, those with a declining prostate-specific antigen (PSA) continued on intermittent testosterone therapy monotherapy. Castrating therapy was continued to suppress endogenous testosterone production, allowing for rapid cycling from supraphysiologic to near-castrate serum testosterone levels, a strategy termed bipolar androgen therapy (BAT). BAT was well tolerated and resulted in high rates of PSA (7 of 14 evaluable patients) and radiographic responses (5 of 10 evaluable patients). Although all men showed eventual PSA progression, four men remained on BAT for ≥1 year. All patients (10 of 10) demonstrated PSA reductions upon receiving androgen-ablative therapies after BAT, suggesting that BAT may also restore sensitivity to ADTs. BAT shows promise as treatment for CRPC and should be further evaluated in larger trials. PMID:25568070

  10. Prognostic value of blood mRNA expression signatures in castration-resistant prostate cancer: a prospective, two-stage study

    PubMed Central

    Olmos, David; Brewer, Daniel; Clark, Jeremy; Danila, Daniel C; Parker, Chris; Attard, Gerhardt; Fleisher, Martin; Reid, Alison H M; Castro, Elena; Sandhu, Shahneen K; Barwell, Lorraine; Oommen, Nikhil Babu; Carreira, Suzanne; Drake, Charles G; Jones, Robert; Cooper, Colin S; Scher, Howard I; de Bono, Johann S

    2016-01-01

    Summary Background Biomarkers are urgently needed to dissect the heterogeneity of prostate cancer between patients to improve treatment and accelerate drug development. We analysed blood mRNA expression arrays to identify patients with metastatic castration-resistant prostate cancer with poorer outcome. Methods Whole blood was collected into PAXgene tubes from patients with castration-resistant prostate cancer and patients with prostate cancer selected for active surveillance. In stage I (derivation set), patients with castration-resistant prostate cancer were used as cases and patients under active surveillance were used as controls. These patients were recruited from The Royal Marsden Hospital NHS Foundation Trust (Sutton, UK) and The Beatson West of Scotland Cancer Centre (Glasgow, UK). In stage II (validation-set), patients with castration-resistant prostate cancer recruited from the Memorial Sloan-Kettering Cancer Center (New York, USA) were assessed. Whole-blood RNA was hybridised to Affymetrix U133plus2 microarrays. Expression profiles were analysed with Bayesian latent process decomposition (LPD) to identify RNA expression profiles associated with castration-resistant prostate cancer subgroups; these profiles were then confirmed by quantative reverse transcriptase (qRT) PCR studies and correlated with overall survival in both the test-set and validation-set. Findings LPD analyses of the mRNA expression data divided the evaluable patients in stage I (n=94) into four groups. All patients in LPD1 (14 of 14) and most in LPD2 (17 of 18) had castration-resistant prostate cancer. Patients with castration-resistant prostate cancer and those under active surveillance comprised LPD3 (15 of 31 castration-resistant prostate cancer) and LDP4 (12 of 21 castration-resistant prostate cancer). Patients with castration-resistant prostate cancer in the LPD1 subgroup had features associated with worse prognosis and poorer overall survival than patients with castration-resistant

  11. [Prostate cancer-the role of docetaxel on castration-resistant prostate cancer: evaluation of efficacy and subsequent treatment].

    PubMed

    Suzuki, Kazuhiro

    2012-10-01

    Docetaxel is used as a standard therapy for castration-resistant prostate cancer(CRPC). A recent report on the safety and efficacy of decetaxel, based on post-marketing surveillance in Japan, showed similar profiles of PSA response and adverse events. For the determination of efficacy, PSA 30% or 50% response, and an imaging examination are evaluated. One most understand the specific patterns of PSA levels, ie, PSA flare, the transient increase of PSA, and PSA stabilization. Docetaxel would be discontinued based on treatment efficacy, further treatment modalities, adverse events, etc. Now that new hormonal and cytotoxic agents are under development, we must accumulate clinical features of patients treated with docetaxel to construct a better future treatment strategy for CRPC. PMID:23064057

  12. 11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored

    PubMed Central

    Pretorius, Elzette; Africander, Donita J.; Vlok, Maré; Quanson, Jonathan

    2016-01-01

    Dihydrotestosterone (DHT) is regarded as the most potent natural androgen and is implicated in the development and progression of castration resistant prostate cancer (CRPC). Under castrate conditions, DHT is produced from the metabolism of the adrenal androgen precursors, DHEA and androstenedione. Recent studies have shown that the adrenal steroid 11β-hydroxyandrostenedione (11OHA4) serves as the precursor to the androgens 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT). In this study we comprehensively assess the androgenic activity of 11KT and 11KDHT. This is the first study, to our knowledge, to show that 11KT and 11KDHT, like T and DHT, are potent and efficacious agonists of the human androgen receptor (AR) and induced both the expression of representative AR-regulated genes as well as cellular proliferation in the androgen dependent prostate cancer cell lines, LNCaP and VCaP. Proteomic analysis revealed that 11KDHT regulated the expression of more AR-regulated proteins than DHT in VCaP cells, while in vitro conversion assays showed that 11KT and 11KDHT are metabolized at a significantly lower rate in both LNCaP and VCaP cells when compared to T and DHT, respectively. Our findings show that 11KT and 11KDHT are bona fide androgens capable of inducing androgen-dependant gene expression and cell growth, and that these steroids have the potential to remain active longer than T and DHT due to the decreased rate at which they are metabolised. Collectively, our data demonstrates that 11KT and 11KDHT likely play a vital, but overlooked, role in the development and progression of CRPC. PMID:27442248

  13. Cost-effectiveness analysis of abiraterone and sipuleucel-T in asymptomatic metastatic castration-resistant prostate cancer.

    PubMed

    Gong, Cynthia L; Hay, Joel W

    2014-10-01

    Of patients diagnosed with prostate cancer, 0% to 20% experience disease progression to metastatic castration-resistant prostate cancer (mCRPC). Recently, 4 novel therapies have been introduced for the treatment of mCRPC; of these, abiraterone and sipuleucel-T have been studied in the asymptomatic, pre-docetaxel population. Both have shown clinical benefits compared with placebo. This study evaluated the cost-effectiveness of abiraterone acetate and sipuleucel-T compared with prednisone in asymptomatic, pre-docetaxel mCRPC from a US societal perspective. A Markov model was constructed to simulate stable disease, progressed disease, and death. Survival and event rates were derived from published clinical trial data. Costs were derived from the literature and government reimbursement schedules. Outcomes were measured as average cost-effectiveness ratios (ACERs), incremental cost-effectiveness ratios (ICERs), and net monetary benefits (NMBs). One-way and probabilistic sensitivity analyses were conducted to test the robustness of the model. The base-case ACER was $114K/quality-adjusted life-years (QALY) for abiraterone, $85K/QALY for sipuleucel-T, and $31K/QALY for prednisone. The base-case ICER was $389K/QALY for abiraterone and $547K/QALY for sipuleucel-T. Prednisone dominates both abiraterone and sipuleucel-T in terms of NMB at willingness-to-pay (WTP) thresholds of $400K or less. One-way sensitivity analyses revealed that the model was most sensitive to overall survival and utility inputs. Probabilistic sensitivity analyses showed abiraterone to be cost-effective 50% or more of the time at a WTP of greater than $400K, whereas sipuleucel-T was cost-effective 50% or more of the time at a WTP of greater than $270K. Neither abiraterone nor sipuleucel-T was found to be cost-effective compared with prednisone in the treatment of asymptomatic, pre-docetaxel mCRPC. PMID:25313181

  14. Androgen receptor functions in castration-resistant prostate cancer and mechanisms of resistance to new agents targeting the androgen axis

    PubMed Central

    Yuan, X; Cai, C; Chen, S; Chen, S; Yu, Z; Balk, SP

    2016-01-01

    The metabolic functions of androgen receptor (AR) in normal prostate are circumvented in prostate cancer (PCa) to drive tumor growth, and the AR also can acquire new growth-promoting functions during PCa development and progression through genetic and epigenetic mechanisms. Androgen deprivation therapy (ADT, surgical or medical castration) is the standard treatment for metastatic PCa, but patients invariably relapse despite castrate androgen levels (castration-resistant PCa, CRPC). Early studies from many groups had shown that AR was highly expressed and transcriptionally active in CRPC, and indicated that steroids from the adrenal glands were contributing to this AR activity. More recent studies showed that CRPC cells had increased expression of enzymes mediating androgen synthesis from adrenal steroids, and could synthesize androgens de novo from cholesterol. Phase III clinical trials showing a survival advantage in CRPC for treatment with abiraterone (inhibitor of the enzyme CYP17A1 required for androgen synthesis that markedly reduces androgens and precursor steroids) and for enzalutamide (new AR antagonist) have now confirmed that AR activity driven by residual androgens makes a major contribution to CRPC, and led to the recent Food and Drug Administration approval of both agents. Unfortunately, patients treated with these agents for advanced CRPC generally relapse within a year and AR appears to be active in the relapsed tumors, but the molecular mechanisms mediating intrinsic or acquired resistance to these AR-targeted therapies remain to be defined. This review outlines AR functions that contribute to PCa development and progression, the roles of intratumoral androgen synthesis and AR structural alterations in driving AR activity in CRPC, mechanisms of action for abiraterone and enzalutamide, and possible mechanisms of resistance to these agents. PMID:23752196

  15. Docetaxel and atrasentan versus docetaxel and placebo for men with advanced castration-resistant prostate cancer (SWOG S0421): a randomised phase 3 trial

    PubMed Central

    Quinn, David I.; Tangen, Catherine M.; Hussain, Maha; Lara, Primo N.; Goldkorn, Amir; Moinpour, Carol M.; Garzotto, Mark G.; Mack, Philip C.; Carducci, Michael A.; Monk, J. Paul; Twardowski, Przemyslaw W.; Van Veldhuizen, Peter J.; Agarwal, Neeraj; Higano, Celestia S.; Vogelzang, Nicholas J.; Thompson, Ian M.

    2014-01-01

    Background Bone metastasis is a hallmark of advanced prostate cancer. The endothelin pathway has a mechanistic role in bone metastases. Atrasentan, an endothelin receptor antagonist, has reported activity in prostate cancer. We assessed the survival impact of atrasentan in castration resistant prostate cancer (CRPC) patients with bone metastases being treated with standard-of-care docetaxel. Methods Men with metastatic CRPC were stratified for progression type (PSA or radiologic), baseline pain, extra skeletal metastases and bisphosphonate use and randomised using double-blinded methodology on a 1:1 ratio to docetaxel with atrasentan or placebo for up to 12 cycles of 3 weeks and treated until progression or unacceptable toxicity. Non-progressing patients were permitted to continue atrasentan or placebo for up to 52 weeks. Co-primary endpoints were progression-free (PFS) and overall survival (OS) where 930 patients are needed to detect a 25% increase in median overall survival of 18 months with the addition of atrasentan (1-sided log-rank α=0.025, power 87%, 4 years accrual, 2.5 additional years of follow-up). Results 1038 patents were accrued. Treatment was halted in April 2011, after an independent data safety monitoring committee pre-planned futility interim analysis. There was no significant difference in OS (HR=1.04 (95% CI 0.90,1.19) p=0.64) or PFS (HR=1.02 (95% CI 0.89,1.16) p=0.81). There was no significant difference between arms for RECIST or PSA response, treatment related deaths or grade 3 or more toxicity. Although 370 patients continued on blinded study drug after cessation of docetaxel, atrasentan did not significantly prolong post-chemotherapy OS in this subset. Interpretation Atrasentan, when added to docetaxel, does not improve overall or progression-free survival in men with castration-resistant prostate cancer and bone metastases. PMID:23871417

  16. Registered report: the androgen receptor induces a distinct transcriptional program in castration-resistant prostate cancer in man

    PubMed Central

    Chronscinski, Denise; Cherukeri, Srujana; Tan, Fraser; Lomax, Joelle; Iorns, Elizabeth

    2015-01-01

    The Prostate Cancer Foundation-Movember Foundation Reproducibility Initiative (PCFMFRI) seeks to address growing concerns about reproducibility in scientific research by conducting replications of recent papers in the field of prostate cancer. This Registered Report describes the proposed replication plan of key experiments from “The Androgen Receptor Induces a Distinct Transcriptional Program in Castration-Resistant Prostate Cancer in Man” by Sharma and colleagues (2013), published in Cancer Cell in 2013. Of thousands of targets for the androgen receptor (AR), the authors elucidated a subset of 16 core genes that were consistently downregulated with castration and re-emerged with castration resistance. These 16 AR binding sites were distinct from those observed in cells in culture. The authors suggested that cellular context can have dramatic effects on downstream transcriptional regulation of AR binding sites. The present study will attempt to replicate Fig. 7C by comparing gene expression of the 16 core genes identified by Sharma and colleagues in xenograft tumor tissue compared to androgen treated LNCaP cells in vitro. The Prostate Cancer Foundation-Movember Foundation Reproducibility Initiative is a collaboration between the Prostate Cancer Foundation, the Movember Initiative, and Science Exchange, and the results of the replications will be published by PeerJ. PMID:26401447

  17. Primary versus castration-resistant prostate cancer: modeling through novel murine prostate cancer cell lines.

    PubMed

    Daoud, Georges; Monzer, Alissar; Bahmad, Hisham; Chamaa, Farah; Hamdar, Layal; Mouhieddine, Tarek H; Shayya, Sami; Eid, Assaad; Kobeissy, Firas; Liu, Yen-Nien; Abou-Kheir, Wassim

    2016-05-17

    Cell lines representing the progression of prostate cancer (PC) from an androgen-dependent to an androgen-independent state are scarce. In this study, we used previously characterized prostate luminal epithelial cell line (Plum), under androgen influence, to establish cellular models of PC progression. Cells derived from orthotopic tumors have been isolated to develop an androgen-dependent (PLum-AD) versus an androgen-independent (PLum-AI) model. Upon immunofluorescent, qRT-PCR and Western blot analyses, PLum-AD cells mostly expressed prostate epithelial markers while PLum-AI cells expressed mesenchymal cell markers. Interestingly, both cell lines maintained a population of stem/progenitor cells. Furthermore, our data suggest that both cell lines are tumorigenic; PLum-AD resulted in an adenocarcinoma whereas PLum-AI resulted in a sarcomatoid carcinoma when transplanted subcutaneously in NOD-SCID mice. Finally, gene expression profiles showed enrichment in functions involved in cell migration, apoptosis, as well as neoplasm invasiveness and metastasis in PLum-AI cells. In conclusion, these data suggest that the newly isolated cell lines represent a new in vitro model of androgen-dependent and -independent PC. PMID:27036046

  18. Use of Prednisone With Abiraterone Acetate in Metastatic Castration-Resistant Prostate Cancer

    PubMed Central

    Yu, Margaret K.; Nguyen, Suzanne; Mundle, Suneel D.

    2014-01-01

    Abiraterone acetate, a prodrug of the CYP17A1 inhibitor abiraterone that blocks androgen biosynthesis, is approved for treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) in combination with prednisone or prednisolone 5 mg twice daily. This review evaluates the basis for the effects of prednisone on mineralocorticoid-related adverse events that arise because of CYP17A1 inhibition with abiraterone. Coadministration with the recommended dose of glucocorticoid compensates for abiraterone-induced reductions in serum cortisol and blocks the compensatory increase in adrenocorticotropic hormone seen with abiraterone. Consequently, 5 mg prednisone twice daily serves as a glucocorticoid replacement therapy when coadministered with abiraterone acetate, analogous to use of glucocorticoid replacement therapy for certain endocrine disorders. We searched PubMed to identify safety concerns regarding glucocorticoid use, placing a focus on longitudinal studies in autoimmune and inflammatory diseases and cancer. In general, glucocorticoid-related adverse events, including bone loss, immunosuppression, hyperglycemia, mood and cognitive alterations, and myopathy, appear dose related and tend to occur at doses and/or treatment durations greater than the low dose of glucocorticoid approved in combination with abiraterone acetate for the treatment of mCRPC. Although glucocorticoids are often used to manage tumor-related symptoms or to prevent treatment-related toxicity, available evidence suggests that prednisone and dexamethasone might also offer modest therapeutic benefit in mCRPC. Given recent improvements in survival achieved for mCRPC with novel agents in combination with prednisone, the risks of these recommended glucocorticoid doses must be balanced with the benefits shown for these regimens. PMID:25361624

  19. Radium-223-Dichloride in Castration Resistant Metastatic Prostate Cancer—Preliminary Results of the Response Evaluation Using F-18-Fluoride PET/CT

    PubMed Central

    Kairemo, Kalevi; Joensuu, Timo

    2015-01-01

    The purpose of this study was to evaluate the outcome after Radium-223-dichloride (223RaCl2) treatment of patients with skeletal metastases of castration resistant prostate cancer using whole-body 18F-Fluoride PET/CT. Sodium 18F-fluoride [18F]-NaF PET/CT was performed prior the treatment of 223RaCl2, after the first cycle and after the sixth cycle. The skeletal metastases were analyzed quantitatively using modified PET response evaluation PERCIST criteria. The patients were also analyzed for S-PSA. All ten patients responded in [18F]-NaF scans after 6 cycles, but interim analysis after the 1st cycle did not give additional information about the outcome. The S-PSA decrease correlated with [18F]-NaF response, only 1 patient demonstrated progressive disease, i.e., >25% increase in S-PSA values during 223RaCl2. Our results (although preliminary) suggest that 18F-Fluoride PET/CT is useful in the follow-up of castration resistant prostate cancer with skeletal metastases. PMID:26854163

  20. MLN2238 synergizes BH3 mimetic ABT-263 in castration-resistant prostate cancer cells by induction of NOXA.

    PubMed

    Wei, Xinghua; Zhou, Ping; Lin, Xuanting; Lin, Yurong; Wu, Sifeng; Diao, Pengfei; Xie, Haiqing; Xie, Keji; Tang, Ping

    2014-10-01

    Patients undergoing androgen blockade therapy develop castration-resistant prostate cancer (CRPC), which is associated with Bcl-2 upregulation and results in disease progression and death. In recent years, promising therapeutic agents, such as the BH3-only mimetic ABT-263 and proteasome inhibitors, have been developed and widely evaluated against a broad spectrum of cancer types, including prostate cancer, alone or in combination with other chemotherapeutic agents. In this study, the antitumor efficacy of ABT-263 and MLN2238 were evaluated as single agents and in combination in four CRPC cell lines: PC3, C4-2B, C4-2, and DU145. The viability of the treated cells and markers of apoptosis were assayed. Protein-protein interactions were analyzed by co-immunoprecipitation in drug-treated cells. Lentivirus-mediated short hairpin RNA was used to knockdown Bax, Mcl-1, and NOXA expressions. We found that ABT-263 and MLN2238 alone exhibited a mild cytotoxicity, and in combination, they elicited a synergistic cytotoxic effect in CRPC cells. The cell apoptosis induced by the combination drug treatment was evidenced by enhanced caspase-3 and Poly (ADP-ribose) polymerase (PARP) cleavage, and annexin-V-positive staining was significantly depleted by Bax knockdown. MLN2238 treatment upregulated NOXA and Mcl-1 expression, leading NOXA/Mcl-1 complexes to disassociate Bak from its complexes with Mcl-1 and enhancing ABT263-triggered Bax activation. NOXA knockdown by short hairpin RNA significantly attenuated the cytotoxicity of ABT-263 and MLN2238 co-administration. In conclusion, MLN2238 and ABT-263 synergistically triggered apoptosis in CRPC cells by upregulating NOXA and activating Bax, indicating a promising therapeutic strategy for the treatment of CRPC. PMID:25027405

  1. Reactive stroma component COL6A1 is upregulated in castration-resistant prostate cancer and promotes tumor growth

    PubMed Central

    Shen, Yi-Jun; Wang, Hong-Kai; Zhang, Gui-Ming; Ye, Ding-Wei

    2015-01-01

    Castration-resistant prostate cancer (CRPC) remains the most critical challenge in the clinical management of prostate cancer (PCa). Reactive stromal changes in PCa are likely involved in the emergence of CRPC. In the present study, we identified a novel oncogene termed COL6A1 which was upregulated in the reactive stroma of CRPC. We established an androgen-independent LNCaP (LNCaP-AI) cell line in steroid-reduced (SR) medium within 2 months. We examined COL6A1 expression with western blot during the LNCaP-AI induction, and studied the function of COL6A1 in vitro and in vivo. Immunohistochemical staining of COL6A1 was performed in ten pairs of androgen-sensitive PCa and CRPC samples. We demonstrated that COL6A1 expression was markedly increased in LNCaP-AI cells and CRPC tissues compared with LNCaP cells and paired androgen-sensitive PCa specimens. In vitro, COL6A1 knockdown resulted in G1-S cell cycle arrest and descended vitality. Overexpression of COL6A1 was associated with accelerated S phase entry and elevated vitality in prostate cancer cells. COL6A1 also promoted tumorigenesis of LNCaP cells in vivo. Taken together, these data suggest an important role of COL6A1 in the molecular etiology of castration-resistant prostate cancer, and support the potential use of COL6A1 in CRPC therapy. PMID:25895032

  2. Docetaxel-related toxicity in metastatic hormone-sensitive and metastatic castration-resistant prostate cancer.

    PubMed

    Schweizer, Michael T; Gulati, Roman; Mostaghel, Elahe A; Nelson, Peter S; Montgomery, R Bruce; Yu, Evan Y; Cheng, Heather H

    2016-07-01

    Docetaxel plus androgen deprivation therapy (ADT) offers a survival benefit in metastatic hormone-sensitive prostate cancer (mHSPC). However, one trial evaluating docetaxel in mHSPC (GETUG-AFU15) showed unexpected toxicity; raising concerns that docetaxel may carry increased toxicity when used to treat mHSPC compared to metastatic castration-resistant prostate cancer (mCRPC). We conducted a retrospective analysis evaluating differences in toxicity based on the clinical state (i.e., mHSPC vs. mCRPC) that docetaxel was used. Patients initiating docetaxel between 1/1/2014 and 7/15/2015 were included, with the former date chosen to coincide with the press release for the first mHSPC study that showed a survival benefit with early docetaxel; ensuring contemporary docetaxel-treated cohorts. Thirty-nine mCRPC and 22 mHSPC patients were included. Compared to mCRPC, mHSPC patients were younger (median years: 66.3 vs. 71.8, P = 0.007); had better performance status (ECOG 0-1: 100 vs. 62 %, P < 0.0001); and used opiates less frequently (29 vs. 66 %, P = 0.04). Neutropenic fevers occurred in 9 and 5 % (P = 0.95) of men with mHSPC and mCRPC, respectively. Other toxicities also occurred at similar rates between cohorts. The incidence of any toxic event was 73 and 67 % (P = 0.84) for men with mHSPC and mCRPC, respectively. Within the mHSPC cohort, neutropenic fevers occurred at a similar rate regardless of the time interval between initiating ADT and the start of docetaxel. We did not observe a significant difference in toxicity between mHSPC and mCRPC patients receiving docetaxel. However, the small sample size and retrospective nature of this study limit our ability to draw definitive conclusions. PMID:27300548

  3. Low β2-adrenergic receptor level may promote development of castration resistant prostate cancer and altered steroid metabolism

    PubMed Central

    Katz, Betina; Kellman, Ralf; Gauthier-Landry, Louis; Fazli, Ladan; Krobert, Kurt Allen; Wang, Wanzhong; Levy, Finn Olav; Bjartell, Anders; Berge, Viktor; Rennie, Paul S.; Mellgren, Gunnar; Mælandsmo, Gunhild Mari; Svindland, Aud; Barbier, Olivier; Taskén, Kristin Austlid

    2016-01-01

    The underlying mechanisms responsible for the development of castration-resistant prostate cancer (CRPC) in patients who have undergone androgen deprivation therapy are not fully understood. This is the first study to address whether β2-adrenergic receptor (ADRB2)- mediated signaling may affect CRPC progression in vivo. By immunohistochemical analyses, we observed that low levels of ADRB2 is associated with a more rapid development of CRPC in a Norwegian patient cohort. To elucidate mechanisms by which ADRB2 may affect CRPC development, we stably transfected LNCaP cells with shRNAs to mimic low and high expression of ADRB2. Two UDP-glucuronosyltransferases, UGT2B15 and UGT2B17, involved in phase II metabolism of androgens, were strongly downregulated in two LNCaP shADRB2 cell lines. The low-ADRB2 LNCaP cell lines displayed lowered glucuronidation activities towards androgens than high-ADRB2 cells. Furthermore, increased levels of testosterone and enhanced androgen responsiveness were observed in LNCaP cells expressing low level of ADRB2. Interestingly, these cells grew faster than high-ADRB2 LNCaP cells, and sustained their low glucuronidation activity in castrated NOD/SCID mice. ADRB2 immunohistochemical staining intensity correlated with UGT2B15 staining intensity in independent TMA studies and with UGT2B17 in one TMA study. Similar to ADRB2, we show that low levels of UGT2B15 are associated with a more rapid CRPC progression. We propose a novel mechanism by which ADRB2 may affect the development of CRPC through downregulation of UGT2B15 and UGT2B17. PMID:26646591

  4. Phase III, Randomized, Double-Blind, Multicenter Trial Comparing Orteronel (TAK-700) Plus Prednisone With Placebo Plus Prednisone in Patients With Metastatic Castration-Resistant Prostate Cancer That Has Progressed During or After Docetaxel-Based Therapy: ELM-PC 5

    PubMed Central

    Fizazi, Karim; Jones, Robert; Oudard, Stephane; Efstathiou, Eleni; Saad, Fred; de Wit, Ronald; De Bono, Johann; Cruz, Felipe Melo; Fountzilas, George; Ulys, Albertas; Carcano, Flavio; Agarwal, Neeraj; Agus, David; Bellmunt, Joaquim; Petrylak, Daniel P.; Lee, Shih-Yuan; Webb, Iain J.; Tejura, Bindu; Borgstein, Niels; Dreicer, Robert

    2015-01-01

    Purpose Orteronel (TAK-700) is an investigational, nonsteroidal, reversible, selective 17,20-lyase inhibitor. This study examined orteronel in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel therapy. Patients and Methods In our study, 1,099 men were randomly assigned in a 2:1 schedule to receive orteronel 400 mg plus prednisone 5 mg twice daily or placebo plus prednisone 5 mg twice daily, stratified by region (Europe, North America [NA], and non-Europe/NA) and Brief Pain Inventory–Short Form worst pain score. Primary end point was overall survival (OS). Key secondary end points (radiographic progression-free survival [rPFS], ≥ 50% decrease of prostate-specific antigen [PSA50], and pain response at 12 weeks) were to undergo statistical testing only if the primary end point analysis was significant. Results The study was unblinded after crossing a prespecified OS futility boundary. The median OS was 17.0 months versus 15.2 months with orteronel-prednisone versus placebo-prednisone (hazard ratio [HR], 0.886; 95% CI, 0.739 to 1.062; P = .190). Improved rPFS was observed with orteronel-prednisone (median, 8.3 v 5.7 months; HR, 0.760; 95% CI, 0.653 to 0.885; P < .001). Orteronel-prednisone showed advantages over placebo-prednisone in PSA50 rate (25% v 10%, P < .001) and time to PSA progression (median, 5.5 v 2.9 months, P < .001) but not pain response rate (12% v 9%; P = .128). Adverse events (all grades) were generally more frequent with orteronel-prednisone, including nausea (42% v 26%), vomiting (36% v 17%), fatigue (29% v 23%), and increased amylase (14% v 2%). Conclusion Our study did not meet the primary end point of OS. Longer rPFS and a higher PSA50 rate with orteronel-prednisone indicate antitumor activity. PMID:25624429

  5. Circulating Endothelial Progenitor Cells in Castration Resistant Prostate Cancer: A Randomized, Controlled, Biomarker Study

    PubMed Central

    Fuereder, Thorsten; Wacheck, Volker; Strommer, Sabine; Horak, Peter; Gerschpacher, Marion; Lamm, Wolfgang; Kivaranovic, Danijel; Krainer, Michael

    2014-01-01

    Background Endothelial progenitor cells (CEPs) and circulating endothelial cells (CECs) are potential biomarkers of response to anti-angiogenic treatment regimens. In the current study, we investigated the effect of docetaxel and sunitinib on CEP/CEC kinetics and clinical response in castration resistant prostate cancer (CRPC) patients. Patients and methods Chemonaive patients with CRPC were enrolled in this study to receive either sunitinib (37.5 mg/d), in combination with docetaxel (75 mg/m2) or docetaxel alone. CEP and CEC kinetics were analyzed for every cycle. The primary objective was to compare CEP/CEC pharmacodynamics between both treatment arms. We also investigated if CEC/CEP spikes, induced by MTD docetaxel, are suppressed by sunitinib in patients treated with docetaxel/sunitinib relative to docetaxel monotherapy. Results A total of 27 patients were enrolled. We observed a significant increase of CEP/CEC (total/viable) counts over time within each cycle (coefficients 0.29233, 0.22092 and 0.26089, respectively; p<0.001). However, no differences between the treatment groups, in terms of CEP and CEC kinetics, were detected. In the docetaxel monotherapy arm 4 (30%) patients responded to therapy with a 50% PSA decline, while 9 (64%) patients showed a PSA decline in the combination group (n.s.). The median PFS in the docetaxel monotherapy group was 3.1 months (2.6–3.6 months, 95% CI) and 6.2 months (4.9–7.4 months, 95% CI; p = 0.062) in the combination arm. Sunitinib/docetaxel was reasonably well tolerated and toxicity manageable. Conclusion In summary, no significant differences in CEC and CEP kinetics between the treatment arms were observed, although a highly significant increase of CEPs/CECs within each cycle over time was detected. These results mirror the challenge we have to face when employing anti-angiogenic strategies in CRPC. Additional preclinical research is needed to elucidate the underlying molecular mechanisms. However, docetaxel

  6. Treatment Sequences and Pharmacy Costs of 2 New Therapies for Metastatic Castration-Resistant Prostate Cancer

    PubMed Central

    Ellis, Lorie A.; Lafeuille, Marie-Hélène; Gozalo, Laurence; Pilon, Dominic; Lefebvre, Patrick; McKenzie, Scott

    2015-01-01

    Background The approval of new therapies for metastatic castration-resistant prostate cancer (mCRPC), including the oral agents abiraterone acetate and enzalutamide, has altered the standard of care for patients with mCRPC. Little information exists regarding the sequences in which new therapies for mCRPC with evidence of survival benefits are used. Objective To describe the sequence of medication use for patients with mCRPC as observed in 3 healthcare data sets. Methods Three healthcare claims data sets were used to identify patients with mCRPC who had no previous use of and were newly initiating 1 of the 2 oral study drugs (ie, abiraterone acetate or enzalutamide). The index date was the first study drug claim after September 1, 2012. Patients were followed until the data cutoff or until being lost to follow-up. Descriptive statistics summarized the proportion of patients receiving 1 line of therapy versus ≥2 lines of therapy. The use of a corticosteroid and the mean monthly pharmacy costs of abiraterone acetate or enzalutamide during the follow-up period were compared between the cohorts. Results A total of 3525 patients with mCRPC were identified from data set 1, 499 patients from data set 2, and 1949 patients from data set 3. The first-line use of abiraterone acetate was observed in 74%, 82%, and 80% of data sets 1, 2, and 3, respectively, and the first-line use of enzalutamide was seen in 26%, 18%, and 20%, respectively, of these same populations. The concomitant use of corticosteroids was observed in patients receiving first-line abiraterone acetate and in patients receiving first-line enzalutamide in all 3 data sets. After September 2012, abiraterone acetate was the most frequently administered therapy for mCRPC among the 2 oral agents, abiraterone acetate and enzalutamide. The monthly pharmacy costs associated with abiraterone acetate were significantly lower than those associated with enzalutamide in all 3 data sets. Conclusions Based on the data used

  7. Radionuclide Therapies in Prostate Cancer: Integrating Radium-223 in the Treatment of Patients With Metastatic Castration-Resistant Prostate Cancer.

    PubMed

    Nilsson, Sten

    2016-02-01

    Metastatic castration-resistant prostate cancer (mCRPC) frequently metastasizes to the bone, often resulting in painful skeletal events, reduced quality of life, and reduced survival. The beta-emitting radiopharmaceuticals strontium-89 and samarium-153 alleviated pain in mCRPC patients with widespread skeletal metastases and have been associated with myelotoxicity. Radium-223, a first-in-class alpha-emitting radiopharmaceutical, prolonged overall survival, delayed symptomatic skeletal events, and improved quality of life, versus placebo, in patients with CRPC and symptomatic bone metastases and no visceral metastases. Radium-223 provided survival benefit to patients with CRPC and symptomatic bone metastases, regardless of prior docetaxel use. Importantly, prostate-specific antigen level and pain palliation were not a measure of radium-223 treatment response and should not alter the decision to administer all six radium-223 injections, the recommended regimen for survival benefit. Radium-223 was generally well tolerated, leading to ongoing clinical trials in combination with other therapeutics. Thus, radium-223 is a valuable addition to the mCRPC treatment armamentarium. PMID:26779616

  8. The Influence of Prednisone on the Efficacy of Docetaxel in Men with Metastatic Castration-Resistant Prostate Cancer

    PubMed Central

    Teply, Benjamin A.; Luber, Brandon; Denmeade, Samuel R.; Antonarakis, Emmanuel S.

    2015-01-01

    BACKGROUND Prednisone and other corticosteroids can provide palliation and tumor responses in patients with prostate cancer. The combination of docetaxel and prednisone was the first treatment shown to prolong survival in men with metastatic castration-resistant prostate cancer (mCRPC). Since the approval of docetaxel in 2004, additional treatments are available, including abiraterone, which is also administered with prednisone. Therefore, patients are increasingly likely to have prednisone therapy several times throughout their disease course, and the contribution of prednisone to the efficacy of docetaxel is unknown. METHODS We conducted a retrospective study of patients with mCPRC treated with docetaxel at our institution between 2004–2014. Patients were divided into 2 cohorts based upon whether prednisone was co-administered with docetaxel. Cohorts were further stratified based upon prior prednisone (with abiraterone) or hydrocortisone (with ketoconazole) use. The primary endpoint was clinical/radiographic progression-free survival (PFS). The secondary endpoints were >50% PSA response rate and PSA progression-free survival (PSA-PFS). A multivariable cox regression model was constructed to determine if prednisone use was independently predictive of PFS. RESULTS We identified 200 consecutive patients for inclusion in the study: 131 men received docetaxel with prednisone and 69 received docetaxel alone. The docetaxel-prednisone cohort had superior PFS compared to the docetaxel-alone cohort (median PFS: 7.8 vs 6.2 months, HR 0.68 [95% CI 0.48–0.97], p=0.03). Prednisone was associated with a reduced risk of progression on docetaxel in the propensity score-weighted multivariable Cox model (p=0.002). Among abiraterone- or ketoconazole-pretreated patients, no difference in PFS was observed between prednisone-containing and non-prednisone containing cohorts (median PFS: 7.1 vs 6.3 months, HR 0.96 [95% CI 0.59–1.57], p=0.87). CONCLUSIONS The incorporation of

  9. Cabazitaxel Plus Prednisone With Octreotide For Castration-Resistant Prostate Cancer (CRPC) Previously Treated With Docetaxel

    ClinicalTrials.gov

    2014-11-21

    Diarrhea; Hormone-resistant Prostate Cancer; Recurrent Prostate Cancer; Stage I Prostate Cancer; Stage IIA Prostate Cancer; Stage IIB Prostate Cancer; Stage III Prostate Cancer; Stage IV Prostate Cancer

  10. [177Lu-PSMA-617 therapy, dosimetry and follow-up in patients with metastatic castration-resistant prostate cancer].

    PubMed

    Fendler, Wolfgang P; Kratochwil, Clemens; Ahmadzadehfar, Hojjat; Rahbar, Kambiz; Baum, Richard P; Schmidt, Matthias; Pfestroff, Andreas; Lützen, Ulf; Prasad, Vikas; Heinzel, Alexander; Heuschkel, Martin; Ruf, Juri; Bartenstein, Peter; Krause, Bernd J

    2016-06-28

    Radioligand therapy (RLT) using 177Lu labelled inhibitors of the prostate-specific membrane antigen (177Lu-PSMA) is performed in patients with metastatic castration-resistant prostate cancer (mCRPC) after exhaustion of other options. German University Clinics offer RLT since 2013 on a compassionate use basis. The present consensus document includes recommendations for RLT with 177Lu-PSMA-617. These consensus statements were developed by an expert panel formed by the German Society of Nuclear Medicine (DGN) in December 2015. Statements include recommendations for indication, baseline tests, therapy protocol, concomitant therapy, dosimetry, and follow-up. Consensus recommendations aim to inform the attending medical staff, standardize 177Lu-PSMA-617 RLT, and improve quality of individual patient care. PMID:27350005

  11. Androgen receptor splice variant 7 (AR-V7) and drug efficacy in castration-resistant prostate cancer: Biomarker for treatment selection exclusion or inclusion?

    PubMed

    Leibrand, Crystal R; Price, Douglas K; Figg, William D

    2016-05-01

    Currently there are no molecular biomarkers used to help guide treatment selection for those patients with castration-resistant prostate cancer. A recent study published in JAMA Oncology (Antonarakis et al.) presents evidence supporting the potential use of androgen receptor splice variant 7 as a biomarker for optimal treatment selection in this population. PMID:26985596

  12. Gradual reduction of testosterone using a gonadotropin-releasing hormone vaccination delays castration resistance in a prostate cancer model

    PubMed Central

    Barranco, Jesús A. Junco; Millar, Robert P.; Fuentes, Franklin; Bover, Eddy; Pimentel, Eulogio; Basulto, Roberto; Calzada, Lesvia; Morán, Rolando; Rodríguez, Ayni; Garay, Hilda; Reyes, Osvaldo; Castro, Maria D.; Bringas, Ricardo; Arteaga, Niurka; Toudurí, Henio; Rabassa, Mauricio; Fernández, Yairis; Serradelo, Andrés; Hernández, Eduardo; Guillén, Gerardo E.

    2016-01-01

    In a previous study aimed to design a novel prostate cancer vaccine, the authors of the present study demonstrated the advantage of combining the adjuvants Montanide ISA 51 with very small size proteoliposomes (VSSP) to promote a significant humoral immune response to gonadotropin-releasing hormone (GnRH) in healthy animals. The present study compared the efficacy of this vaccine formulation versus the standard treatment currently available in terms of preventing the development of tumors in DD/S mice injected with Shionogi carcinoma (SC) 115 cells. The results demonstrated that 5 non-vaccinated control mice exhibited a fast tumor growth, and succumbed to the disease within 19–31 days. Mice immunized with the GnRH/Montanide ISA 51/VSSP vaccine exhibited a moderate decline in testosterone levels that was associated with a decrease in anti-GnRH antibody titers, which lead to a sustained tumor growth inhibition. In total, 2 mice in the immunized group exhibited complete remission of the tumor for the duration of the present study. In addition, castrated mice, which were used as a control for standard hormonal therapy, exhibited an accelerated decrease in tumor size. However, tumor relapse was observed between days 50 and 54, and between days 65 and 85, following the injection of SC 155 cells. Therefore, these mice were sacrificed at day 90. The present study concludes that the slow and moderate reduction of testosterone levels observed using the GnRH-based vaccine may delay the appearance of castration resistance in a Shionogi prostate cancer model. These findings suggest that this vaccine may be used to delay castration resistance in patients with prostate cancer. PMID:27446378

  13. Phase II study of lutetium-177 labeled anti-prostate-specific membrane antigen (PSMA) monoclonal antibody J591 for metastatic castration-resistant prostate cancer

    PubMed Central

    Tagawa, Scott T.; Milowsky, Matthew I.; Morris, Michael; Vallabhajosula, Shankar; Christos, Paul; Akhtar, Naveed H.; Osborne, Joseph; Goldsmith, Stanley J.; Larson, Steve; Taskar, Neeta Pandit; Scher, Howard I.; Bander, Neil H.; Nanus, David M.

    2013-01-01

    Purpose To assess the efficacy of a single infusion of radiolabeled anti-prostate specific membrane antigen monoclonal antibody J591 (177Lu-J591) by PSA decline, measurable disease response, and survival. Experimental Design In this dual-center phase II study, 2 cohorts with progressive metastatic castration-resistant prostate cancer received one dose of 177Lu-J591 (15 patients at 65 mCi/m2, 17 at 70 mCi/m2) with radionuclide imaging. Expansion cohort (n=15) received 70 mCi/m2 to verify response rate and examine biomarkers. Results 47 patients who progressed after hormonal therapies (55.3% also received prior chemotherapy) received 177Lu-J591. 10.6% experienced ≥ 50% decline in PSA, 36.2% experienced ≥ 30% decline, and 59.6% experienced any PSA decline following their single treatment. One of 12 with measurable disease experienced a partial radiographic response (8 with stable disease). Sites of prostate cancer metastases were targeted in 44 of 47 (93.6%) as determined by planar imaging. All experienced reversible hematologic toxicity with grade 4 thrombocytopenia occurring in 46.8% (29.8% received platelet transfusions) without significant hemorrhage. 25.5% experienced grade 4 neutropenia with 1 episode of febrile neutropenia. The phase I maximum tolerated dose (70 mCi/m2) resulted in more 30% PSA declines (46.9% vs 13.3%, p=0.048) and longer survival (21.8 vs 11.9 months, p=0.03), but also more grade 4 hematologic toxicity and platelet transfusions. No serious non-hematologic toxicity occurred. Those with poor PSMA imaging were less likely to respond. Conclusion A single dose of 177Lu-J591 was well-tolerated with reversible myelosuppression. Accurate tumor targeting and PSA responses were seen with evidence of dose-response. Imaging biomarkers appear promising. PMID:23714732

  14. Cotargeting Polo-Like Kinase 1 and the Wnt/β-Catenin Signaling Pathway in Castration-Resistant Prostate Cancer.

    PubMed

    Li, Jie; Karki, Anju; Hodges, Kurt B; Ahmad, Nihal; Zoubeidi, Amina; Strebhardt, Klaus; Ratliff, Timothy L; Konieczny, Stephen F; Liu, Xiaoqi

    2015-12-01

    The Wnt/β-catenin signaling pathway has been identified as one of the predominantly upregulated pathways in castration-resistant prostate cancer (CRPC). However, whether targeting the β-catenin pathway will prove effective as a CRPC treatment remains unknown. Polo-like kinase 1 (Plk1) is a critical regulator in many cell cycle events, and its level is significantly elevated upon castration of mice carrying xenograft prostate tumors. Indeed, inhibition of Plk1 has been shown to inhibit tumor growth in several in vivo studies. Here, we show that Plk1 is a negative regulator of Wnt/β-catenin signaling. Plk1 inhibition or depletion enhances the level of cytosolic and nuclear β-catenin in human prostate cancer cells. Furthermore, inhibition of Wnt/β-catenin signaling significantly potentiates the antineoplastic activity of the Plk1 inhibitor BI2536 in both cultured prostate cancer cells and CRPC xenograft tumors. Mechanistically, axin2, a negative regulator of the β-catenin pathway, serves as a substrate of Plk1, and Plk1 phosphorylation of axin2 facilitates the degradation of β-catenin by enhancing binding between glycogen synthase kinase 3β (GSK3β) and β-catenin. Plk1-phosphorylated axin2 also exhibits resistance to Cdc20-mediated degradation. Overall, this study identifies a novel Plk1-Wnt signaling axis in prostate cancer, offering a promising new therapeutic option to treat CRPC. PMID:26438599

  15. Cotargeting Polo-Like Kinase 1 and the Wnt/β-Catenin Signaling Pathway in Castration-Resistant Prostate Cancer

    PubMed Central

    Li, Jie; Karki, Anju; Hodges, Kurt B.; Ahmad, Nihal; Zoubeidi, Amina; Strebhardt, Klaus; Ratliff, Timothy L.; Konieczny, Stephen F.

    2015-01-01

    The Wnt/β-catenin signaling pathway has been identified as one of the predominantly upregulated pathways in castration-resistant prostate cancer (CRPC). However, whether targeting the β-catenin pathway will prove effective as a CRPC treatment remains unknown. Polo-like kinase 1 (Plk1) is a critical regulator in many cell cycle events, and its level is significantly elevated upon castration of mice carrying xenograft prostate tumors. Indeed, inhibition of Plk1 has been shown to inhibit tumor growth in several in vivo studies. Here, we show that Plk1 is a negative regulator of Wnt/β-catenin signaling. Plk1 inhibition or depletion enhances the level of cytosolic and nuclear β-catenin in human prostate cancer cells. Furthermore, inhibition of Wnt/β-catenin signaling significantly potentiates the antineoplastic activity of the Plk1 inhibitor BI2536 in both cultured prostate cancer cells and CRPC xenograft tumors. Mechanistically, axin2, a negative regulator of the β-catenin pathway, serves as a substrate of Plk1, and Plk1 phosphorylation of axin2 facilitates the degradation of β-catenin by enhancing binding between glycogen synthase kinase 3β (GSK3β) and β-catenin. Plk1-phosphorylated axin2 also exhibits resistance to Cdc20-mediated degradation. Overall, this study identifies a novel Plk1-Wnt signaling axis in prostate cancer, offering a promising new therapeutic option to treat CRPC. PMID:26438599

  16. Toward a Common Therapeutic Framework in Castration Resistant Prostate Cancer: A Model for Urologic Oncology and Medical Oncology Interaction

    PubMed Central

    de Vere White, Ralph; Lara, Primo N.

    2015-01-01

    The rapid evolution of palliative therapeutic choices in the last few years for patients with advanced castration resistant prostate cancer (CRPC) has resulted in a dilemma currently troubling a few other epithelial malignancies: which systemic agent to choose and at what time? In addition, which specialty specifically directs the delivery of such care – Urology or Medical Oncology – has not been clearly established. Recognizing the lack of consensus, we propose a framework for Urology and Medical Oncology interactions that is founded on models that have succeeded in the past. This approach aims to focus the care on the CRPC patient rather than on his physicians and promises to improve patient outcomes in this disease state. PMID:24316022

  17. Molecular profiling of peripheral blood is associated with circulating tumor cells content and poor survival in metastatic castration-resistant prostate cancer.

    PubMed

    Marín-Aguilera, Mercedes; Reig, Òscar; Lozano, Juan José; Jiménez, Natalia; García-Recio, Susana; Erill, Nadina; Gaba, Lydia; Tagliapietra, Andrea; Ortega, Vanesa; Carrera, Gemma; Colomer, Anna; Gascón, Pedro; Mellado, Begoña

    2015-04-30

    The enumeration of circulating tumor cells (CTCs) in peripheral blood correlates with clinical outcome in castration-resistant prostate cancer (CRPC). We analyzed the molecular profiling of peripheral blood from 43 metastatic CRPC patients with known CTC content in order to identify genes that may be related to prostate cancer progression. Global gene expression analysis identified the differential expression of 282 genes between samples with ≥5 CTCs vs <5 CTCs, 58.6% of which were previously described as over-expressed in prostate cancer (18.9% in primary tumors and 56.1% in metastasis). Those genes were involved in survival functions such as metabolism, signal transduction, gene expression, cell growth, death, and movement. The expression of selected genes was evaluated by quantitative RT-PCR. This analysis revealed a two-gene model (SELENBP1 and MMP9) with a high significant prognostic ability (HR 6; 95% CI 2.61 - 13.79; P<0.0001). The combination of the two-gene signature plus the CTCs count showed a higher prognostic ability than CTCs enumeration or gene expression alone (P<0.05). This study shows a gene expression profile in PBMNC associated with CTCs count and clinical outcome in metastatic CRPC, describing genes and pathways potentially associated with CRPC progression. PMID:25871394

  18. Saracatinib as a Metastasis Inhibitor in Metastatic Castration-Resistant Prostate Cancer: A University of Chicago Phase 2 Consortium and DOD/PCF Prostate Cancer Clinical Trials Consortium Study

    PubMed Central

    Posadas, Edwin M.; Ahmed, Rafi S.; Karrison, Theodore; Szmulewitz, Russell Z.; O’Donnell, Peter H.; Wade, James L.; Shen, James; Gururajan, Murali; Sievert, Margarit; Stadler, Walter M.

    2016-01-01

    BACKGROUND Fyn is a kinase that is upregulated in a subset of metastatic castration-resistant prostate cancer. Saracatinib potently inhibits Fyn activation. We have noted a relationship between Fyn expression and directional motility, a cellular process related to metastasis. As such we hypothesized that treatment with saracatinib would increase the time required to develop new metastatic lesions. METHODS Patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel were eligible for enrollment. This study was executed as a randomized discontinuation trial. During a lead-in phase of two 28-Day cycles, all patients received saracatinib. Afterward, patients with radiographically stable disease were randomized to either saracatinib or placebo. Patients continued treatment until evidence of new metastasis. RESULTS Thirty-one patients were treated. Only 26% of patients had stable disease after 8 weeks and thus proceeded to randomization. This required early termination of the study for futility. The 70% of patients who progressed after the lead-in phase exhibited expansion of existing lesions or decompensation due to clinical progression without new metastatic lesions. Fatigue was reported in more than 25% of patients (all grades) with only two patients experiencing grade 3 toxicity. Other grade 3 adverse events included dehydration, thrombocytopenia, and weakness. CONCLUSIONS This study was unable to determine if saracatinib had potential as metastasis inhibitor. Metastasis inhibition by saracatinib may still be viable in an earlier time in the disease history. PMID:26493492

  19. Androgen Receptor Splice Variant 7 and Efficacy of Taxane Chemotherapy in Patients With Metastatic Castration-Resistant Prostate Cancer

    PubMed Central

    Antonarakis, Emmanuel S.; Lu, Changxue; Luber, Brandon; Wang, Hao; Chen, Yan; Nakazawa, Mary; Nadal, Rosa; Paller, Channing J.; Denmeade, Samuel R.; Carducci, Michael A.; Eisenberger, Mario A.; Luo, Jun

    2015-01-01

    IMPORTANCE We previously showed that detection of androgen receptor splice variant 7 (AR-V7) in circulating tumor cells (CTCs) from men with castration-resistant prostate cancer (CRPC) was associated with primary resistance to enzalutamide and abiraterone therapy, but the relevance of AR-V7 status in the context of chemotherapy is unknown. OBJECTIVE To investigate whether AR-V7–positive patients would retain sensitivity to taxane chemotherapy and whether AR-V7 status would have a differential impact on taxane-treated men compared with enzalutamide- or abiraterone-treated men. DESIGN, SETTING, AND PARTICIPANTS We examined CTCs for AR-V7 mRNA using a reverse-transcription polymerase chain reaction assay. From January 2013 to July 2014, we prospectively enrolled patients with metastatic CRPC initiating taxane chemotherapy (docetaxel or cabazitaxel) at a single academic institution (Johns Hopkins). Our prespecified statistical plan required a sample size of 36 taxane-treated men. MAIN OUTCOMES AND MEASURES We evaluated associations between AR-V7 status and prostate-specific antigen (PSA) response rates. PSA progression-free survival (PSA PFS), and clinical and/or radiographic progression-free survival (PFS). After incorporating updated data from our prior study of 62 patients treated with enzalutamide or abiraterone, we also investigated the interaction between AR-V7 status (positive or negative) and treatment type (taxane vs enzalutamide or abiraterone). RESULTS Of 37 taxane-treated patients enrolled. 17 (46%) had detectable AR-V7 in CTCs. Prostate-specific antigen responses were achieved in both AR-V7–positive and AR-V7–negative men (41% vs 65%; P = .19) Similarly, PSA PFS (hazard ratio [HR], 1.7, 95% CI, 0.6-5.0; P = .32) and PFS (HR, 2.7, 95% CI, 0.8-8.8; P = .11) were comparable in AR-V7–positive and AR-V7–negative patients. A significant interaction was observed between AR-V7 status and treatment type (P < .001). Clinical outcomes were superior with

  20. A phase II trial of personalized peptide vaccination in castration-resistant prostate cancer patients: prolongation of prostate-specific antigen doubling time

    PubMed Central

    2013-01-01

    Background Cancer vaccine is one of the attractive treatment modalities for patients with castration-resistant prostate cancer (CRPC). However, because of delayed immune responses, its clinical benefits, besides for overall survival (OS), are not well captured by the World Health Organization (WHO) and Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Several surrogate markers for evaluation of cancer vaccine, including prostate-specific antigen doubling time (PSADT), are currently sought. The purpose of this study was to assess prospectively the PSA kinetics and immune responses, as well as the efficacy, safety, and biomarkers of personalized peptide vaccination (PPV) in progressive CRPC. Methods One hundred patients with progressive CRPC were treated with PPV using 2–4 positive peptides from 31 candidate peptides determined by both human leukocyte antigen (HLA) class IA types and the levels of immunoglobulin G (IgG) against each peptide. The association between immune responses and PSADT as well as overall survival (OS) was studied. Results PPV was safe and well tolerated in all patients with a median survival time of 18.8 months. Peptide-specific IgG and T-cell responses strongly correlated with PSADT (p < 0.0001 and p = 0.0007, respectively), which in turn showed correlation with OS (p = 0.018). Positive IgG responses and prolongation of PSADT during PPV were also significantly associated with OS (p = 0.001 and p = 0.004) by multivariate analysis. Conclusions PSADT could be an appropriate surrogate marker for evaluation of the clinical benefit of cancer vaccine. Further randomized trials are needed to confirm these results. Trial registration UMIN000001850 PMID:24373380

  1. [Efficacy and Prognostic Factors of Estracyt ® in Patients with Castration-Resistant Prostate Cancer (CRPC) : From the Data Analysis of Estracyt ® Special Drug Use Investigation].

    PubMed

    Murachi, Kazunori; Kumagai, Tadashi; Masuda, Tatsunori; Nakanishi, Tadaharu; Tanaka, Shinichi; Tajima, Koyuki; Takebe, Yasushi; Oda, Takayuki

    2016-06-01

    Estracyt○R (estramustine phosphate) is a medical drug for prostate cancer with cytotoxic activity causing disruption of microtubule organization and indirect androgen production suppressing activity by its metabolite, estradiol. Based on the data obtained from the Estracyt○R Special Drug Use Investigation which surveyed the clinical efficacy and safety of Estracyt○R in patients with prostate cancer whose relapse of prostate cancer after combined androgen blockade (CAB) therapy was confirmed, we evaluated the progression-free survival, prognostic factor, decrease in prostate specific antigen (PSA) level and safety. This surveillance was conducted at 147 institutions nationwide between October, 2010 and September, 2013 and clinical efficacy was evaluated in 239 cases and safety in 329 cases. The median duration of progression-free survival, PSA progression-free survival and PSA response were 169 days (95%CI, 142-190), 197 days (95%CI, 169-267) and 385 days, respectively. The decrease in PSA level was observed in 125 cases (52.3%). Rate of PSA decline >50 and >25% were 18.4 and 43.1, respectively, and rate of PSA best response (PSA decline > 50%) was 32.6%. Multivariate analysis demonstrated that long duration of prior CAB therapy, Estracyt○R - pretreatment PSA value and bone metastasis influenced progression-free survival significantly. Adverse events were observed in 127 cases (38.6%). The major adverse events were anorexia which was observed in 35 cases (10.9%), gastrointestinal disorders observed in 32 cases (9.7%), abnormal laboratory test values observed in 31 cases (9.4%) and gynecomastia observed in 16 cases (4.9%). These results suggest the clinical efficacy and safety of Estracyt○R for chemotherapy-naïve castration-resistant prostate cancer (CRPC), and Estracyt○R is regarded as one of the treatment options for patients with CRPC, especially for patients who had long duration of prior CAB therapy. PMID:27452492

  2. Hypoxic Tumor Kinase Signaling Mediated by STAT5A in Development of Castration-Resistant Prostate Cancer

    PubMed Central

    Røe, Kathrine; Bratland, Åse; Vlatkovic, Ljiljana; Ragnum, Harald Bull; Saelen, Marie Grøn; Olsen, Dag Rune; Marignol, Laure; Ree, Anne Hansen

    2013-01-01

    In this study, we hypothesized that androgen-deprivation therapy (ADT) in prostate cancer, although initially efficient, induces changes in the tumor kinome, which subsequently promote development of castration-resistant (CR) disease. Recognizing the correlation between tumor hypoxia and poor prognosis in prostate cancer, we further hypothesized that such changes might be influenced by hypoxia. Microarrays with 144 kinase peptide substrates were applied to analyze CWR22 prostate carcinoma xenograft samples from ADT-naïve, androgen-deprived (AD), long-term AD (ADL), and CR disease stages. The impact of hypoxia was assessed by matching the xenograft kinase activity profiles with those acquired from hypoxic and normoxic prostate carcinoma cell cultures, whereas the clinical relevance was evaluated by analyzing prostatectomy tumor samples from patients with locally advanced disease, either in ADT-naïve or early CR disease stages. By using this novel peptide substrate microarray method we revealed high kinase activity mediated by signal transducer and activator of transcription 5A (STAT5A) in CR prostate cancer. Additionally, we uncovered high STAT5A kinase activity already in regressing ADL xenografts, before renewed CR growth was evidenced. Finally, since increased STAT5A kinase activity also was detected after exposing prostate carcinoma cells to hypoxia, we propose long-term ADT to induce tumor hypoxia and stimulate STAT5A kinase activity, subsequently leading to renewed CR tumor growth. Hence, the study detected STAT5A as a candidate to be further investigated for its potential as marker of advanced prostate cancer and as possible therapeutic target protein. PMID:23675504

  3. A randomised phase 2 study combining LY2181308 sodium (survivin antisense oligonucleotide) with first-line docetaxel/prednisone in patients with castration-resistant prostate cancer.

    PubMed

    Wiechno, Paweł; Somer, Bradley G; Mellado, Begoña; Chłosta, Piotr L; Cervera Grau, José Manuel; Castellano, Daniel; Reuter, Christoph; Stöckle, Michael; Kamradt, Jörn; Pikiel, Joanna; Durán, Ignacio; Wedel, Steffen; Callies, Sophie; André, Valérie; Hurt, Karla; Brown, Jacqueline; Lahn, Michael; Heinrich, Bernhard

    2014-03-01

    Castration-resistant prostate cancer (CRPC) is partially characterised by overexpression of antiapoptotic proteins, such as survivin. In this phase 2 study, patients with metastatic CRPC (n=154) were randomly assigned (1:2 ratio) to receive standard first-line docetaxel/prednisone (control arm) or the combination of LY2181308 with docetaxel/prednisone (experimental arm). The primary objective was to estimate progression-free survival (PFS) for LY2181308 plus docetaxel. Secondary efficacy measures included overall survival (OS), several predefined prostate-specific antigen (PSA)-derived end points, and Brief Pain Inventory (BPI) and Functional Assessment of Cancer Therapy-Prostate (FACT-P) scores. The median PFS of treated patients for the experimental arm (n=98) was 8.64 mo (90% confidence interval [CI], 7.39-10.45) versus 9.00 mo (90% CI, 7.00-10.09) in the control arm (n=51; p=0.755). The median OS for the experimental arm was 27.04 mo (90% CI, 19.94-33.41) compared with 29.04 mo (90% CI, 20.11-39.26; p=0.838). The PSA responses (≥ 50% PSA reduction), BPI, and FACT-P scores were similar in both arms. In the experimental arm, patients had a numerically higher incidence of grades 3-4 neutropenia, anaemia, thrombocytopenia, and sensory neuropathy. In conclusion, this study failed to detect a difference in efficacy between the two treatment groups. PMID:24246407

  4. Phase I Study of the Prolactin Receptor Antagonist LFA102 in Metastatic Breast and Castration-Resistant Prostate Cancer

    PubMed Central

    Machiels, Jean-Pascal; Suárez, Cristina; Lewis, Nancy; Higgins, Michaela; Wisinski, Kari; Awada, Ahmad; Maur, Michela; Stein, Mark; Hwang, Andy; Mosher, Rebecca; Wasserman, Ernesto; Wu, Gang; Zhang, Hefei; Zieba, Renata; Elmeliegy, Mohamed

    2016-01-01

    Lessons Learned Despite evidence for a role for prolactin signaling in breast and prostate tumorigenesis, a prolactin receptor-binding monoclonal antibody has not produced clinical efficacy. Increased serum prolactin levels may be a biomarker for prolactin receptor inhibition. Results from the pharmacokinetic and pharmacodynamics (PD) studies suggest that inappropriately long dosing intervals and insufficient exposure to LFA102 may have resulted in lack of antitumor efficacy. Based on preclinical data, combination therapy of LFA102 with those novel agents targeting hormonal pathways in metastatic castration-resistant prostate cancer and metastatic breast cancer is promising. Given the PD evidence of prolactin receptor blockade by LFA102, this drug has the potential to be used in conditions such as hyperprolactinemia that are associated with high prolactin levels. Background. Prolactin receptor (PRLR) signaling is implicated in breast and prostate cancer. LFA102, a humanized monoclonal antibody (mAb) that binds to and inhibits the PRLR, has exhibited promising preclinical antitumor activity. Methods. Patients with PRLR-positive metastatic breast cancer (MBC) or metastatic castration-resistant prostate cancer (mCRPC) received doses of LFA102 at 3–60 mg/kg intravenously once every 4 weeks. Objectives were to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) to investigate the safety/tolerability of LFA102 and to assess pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity. Results. A total of 73 patients were enrolled at 5 dose levels. The MTD was not reached because of lack of dose-limiting toxicities. The RDE was established at 60 mg/kg based on PK and PD analysis and safety data. The most common all-cause adverse events (AEs) were fatigue (44%) and nausea (33%) regardless of relationship. Grade 3/4 AEs reported to be related to LFA102 occurred in 4% of patients. LFA102 exposure increased approximately dose

  5. Early outcome prediction on 18F-fluorocholine PET/CT in metastatic castration-resistant prostate cancer patients treated with abiraterone

    PubMed Central

    De Giorgi, Ugo; Caroli, Paola; Burgio, Salvatore L.; Menna, Cecilia; Conteduca, Vincenza; Bianchi, Emanuela; Fabbri, Francesca; Carretta, Elisa; Amadori, Dino; Paganelli, Giovanni; Matteucci, Federica

    2014-01-01

    Objective: We investigated the role of 18F-fluorocholine positron emission tomography/computed tomography (FCH-PET/CT) in the early evaluation of abiraterone and outcome prediction in patients with metastatic castration-resistant prostate cancer (CRPC). Patient and methods: Forty-three patients with metastatic CRPC progressing after docetaxel received abiraterone 1,000 mg daily with prednisone 5 mg twice daily. Patients were evaluated monthly for serological PSA response and safety. FCH-PET/CT was done at baseline and after 3 to 6 weeks. Univariate and multivariate Cox regression models addressed potential predictors of progression-free survival (PFS) and overall survival (OS). Results: Declines in PSA level of ≥50% were seen in 21 of 43 (49%) patients. Forty-two patients were evaluable for FCH-PET/CT response. FCH-PET/CT bone flare was observed in 4 of 42 (10%) evaluable patients. In univariate analysis, PSA decline and FCH-PET/CT response predicted PFS, while PSA decline and FCH-PET/CT (progression vs non progression) predicted OS. In multivariate analysis, only FCH-PET/CT (progression vs nonprogression) remained significant for PFS and OS (p = 0.022 and p = 0.027, respectively). Conclusion: Early FCH-PET/CT can predict clinical outcome in CRPC beyond PSA response. These data support further studies on FCH-PET/CT for abiraterone monitoring and outcome prediction in patients with CRPC. PMID:25504434

  6. ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer.

    PubMed

    Wang, Junjian; Zou, June X; Xue, Xiaoqian; Cai, Demin; Zhang, Yan; Duan, Zhijian; Xiang, Qiuping; Yang, Joy C; Louie, Maggie C; Borowsky, Alexander D; Gao, Allen C; Evans, Christopher P; Lam, Kit S; Xu, Jianzhen; Kung, Hsing-Jien; Evans, Ronald M; Xu, Yong; Chen, Hong-Wu

    2016-05-01

    The androgen receptor (AR) is overexpressed and hyperactivated in human castration-resistant prostate cancer (CRPC). However, the determinants of AR overexpression in CRPC are poorly defined. Here we show that retinoic acid receptor-related orphan receptor γ (ROR-γ) is overexpressed and amplified in metastatic CRPC tumors, and that ROR-γ drives AR expression in the tumors. ROR-γ recruits nuclear receptor coactivator 1 and 3 (NCOA1 and NCOA3, also known as SRC-1 and SRC-3) to an AR-ROR response element (RORE) to stimulate AR gene transcription. ROR-γ antagonists suppress the expression of both AR and its variant AR-V7 in prostate cancer (PCa) cell lines and tumors. ROR-γ antagonists also markedly diminish genome-wide AR binding, H3K27ac abundance and expression of the AR target gene network. Finally, ROR-γ antagonists suppressed tumor growth in multiple AR-expressing, but not AR-negative, xenograft PCa models, and they effectively sensitized CRPC tumors to enzalutamide, without overt toxicity, in mice. Taken together, these results establish ROR-γ as a key player in CRPC by acting upstream of AR and as a potential therapeutic target for advanced PCa. PMID:27019329

  7. Interaction between c-jun and Androgen Receptor Determines the Outcome of Taxane Therapy in Castration Resistant Prostate Cancer

    PubMed Central

    Tinzl, Martina; Chen, Binshen; Chen, Shao-Yong; Semenas, Julius; Abrahamsson, Per-Anders; Dizeyi, Nishtman

    2013-01-01

    Taxane based chemotherapy is the standard of care treatment in castration resistant prostate cancer (CRPC). There is convincing evidence that taxane therapy affects androgen receptor (AR) but the exact mechanisms have to be further elucidated. Our studies identified c-jun as a crucial key player which interacts with AR and thus determines the outcome of the taxane therapy given. Docetaxel (Doc) and paclitaxel (Pac) agents showed different effects on LNCaP and LNb4 evidenced by alteration in the protein and mRNA levels of c-jun, AR and PSA. Docetaxel-induced phophorylation of c-jun occurred before JNK phosphorylation which suggests that c-jun phosphorylation is independent of JNK pathways in prostate cancer cells. A xenograft study showed that mice treated with Pac and bicalutamide showed worse outcome supporting our hypothesis that upregulation of c-jun might act as a potent antiapoptotic factor. We observed in our in vitro studies an inverse regulation of PSA- and AR-mRNA levels in Doc treated LNb4 cells. This was also seen for kallikrein 2 (KLK 2) which followed the same pattern. Given the fact that response to taxane therapy is measured by PSA decrease we have to consider that this might not reflect the true activity of AR in CRPC patients. PMID:24260253

  8. Docetaxel-carboxymethylcellulose nanoparticles display enhanced anti-tumor activity in murine models of castration-resistant prostate cancer.

    PubMed

    Hoang, Bryan; Ernsting, Mark J; Murakami, Mami; Undzys, Elijus; Li, Shyh-Dar

    2014-08-25

    Docetaxel (DTX) remains the only effective drug for prolonging survival and improving quality of life of metastatic castration resistant prostate cancer (mCRPC) patients. Despite some clinical successes with DTX-based therapies, advent of cumulative toxicity and development of drug resistance limit its long-term clinical application. The integration of nanotechnology for drug delivery can be exploited to overcome the major intrinsic limitations of DTX therapy for mCRPC. We evaluated whether reformulation of DTX by facile conjugation to carboxymethylcellulose nanoparticles (Cellax) can improve the efficacy and safety of the drug in s.c. and bone metastatic models of CRPC. A single dose of the nanoparticles completely regressed s.c. PC3 tumor xenografts in mice. In addition, Cellax elicited fewer side effects compared to native DTX. Importantly, Cellax did not increase the expression of drug resistance molecules in androgen-independent PC3 prostate cancer cells in comparison with DTX. Lastly, in a bone metastatic model of CRPC, Cellax treatment afforded a 2- to 3-fold improvement in survival and enhancements in quality-of-life of the animals over DTX and saline controls. These results demonstrate the potential of Cellax in improving the treatment of mCRPC. PMID:24853460

  9. Phosphoproteomic profiling identifies focal adhesion kinase as a mediator of docetaxel resistance in castrate-resistant prostate cancer.

    PubMed

    Lee, Brian Y; Hochgräfe, Falko; Lin, Hui-Ming; Castillo, Lesley; Wu, Jianmin; Raftery, Mark J; Martin Shreeve, S; Horvath, Lisa G; Daly, Roger J

    2014-01-01

    Docetaxel remains the standard-of-care for men diagnosed with metastatic castrate-resistant prostate cancer (CRPC). However, only approximately 50% of patients benefit from treatment and all develop docetaxel-resistant disease. Here, we characterize global perturbations in tyrosine kinase signaling associated with docetaxel resistance and thereby develop a potential therapeutic strategy to reverse this phenotype. Using quantitative mass spectrometry-based phosphoproteomics, we identified that metastatic docetaxel-resistant prostate cancer cell lines (DU145-Rx and PC3-Rx) exhibit increased phosphorylation of focal adhesion kinase (FAK) on Y397 and Y576, in comparison with parental controls (DU145 and PC3, respectively). Bioinformatic analyses identified perturbations in pathways regulating focal adhesions and the actin cytoskeleton and in protein-protein interaction networks related to these pathways in docetaxel-resistant cells. Treatment with the FAK tyrosine kinase inhibitor (TKI) PF-00562271 reduced FAK phosphorylation in the resistant cells, but did not affect cell viability or Akt phosphorylation. Docetaxel administration reduced FAK and Akt phosphorylation, whereas cotreatment with PF-00562271 and docetaxel resulted in an additive attenuation of FAK and Akt phosphorylation and overcame the chemoresistant phenotype. The enhanced efficacy of cotreatment was due to increased autophagic cell death, rather than apoptosis. These data strongly support that enhanced FAK activation mediates chemoresistance in CRPC, and identify a potential clinical niche for FAK TKIs, where coadministration with docetaxel may be used in patients with CRPC to overcome chemoresistance. PMID:24194567

  10. Saikosaponin-d: A potential chemotherapeutics in castration resistant prostate cancer by suppressing cancer metastases and cancer stem cell phenotypes.

    PubMed

    Zhong, Di; Zhang, Hui-Jian; Jiang, Yao-Dong; Wu, Peng; Qi, Huan; Cai, Chao; Zheng, Shao-Bin; Dang, Qiang

    2016-06-10

    Androgen deprivation therapy is the gold standard regimen for advanced Prostate cancer (PCa) patients, nevertheless, patients eventually develop into castration-resistant prostate cancer (CRPC). Currently only a few chemotherapeutics are available for CRPC. Therefore, it is critical for identifying a new drug. In this study, we will explore a new agent, Saikosaponin-d (SSd), for CRPC therapy based on its mechanism of action. DU145 and CWR22Rv1 cells representing CRPC were employed in this study. A series of cell, biochemical, and molecular biologic assays such as Immunofluorescence, Zymography, Sphere formation, Colony formation, and MTT were used. Finally, we find SSd can significantly inhibit the growth of PCa cells in both dose- and time-dependent and suppress the colony formation during a long-term drug administration, it also can inhibit their migration and invasion abilities, which was accompanied by reverse the epithelial-mesenchymal transition (EMT) and suppress MMP2/9 expression as well as activities. Furthermore, SSd can suppress cancer stem cell (CSC) phenotypes such as self-renewal ability. Mechanistically, SSd blocks Wnt/β-catenin signaling pathway by decreasing GSK3β phosphorylation to affect EMT and CSC. These findings demonstrate the mechanism of anti-cancer activity of SSd in targeting EMT and CSC, suggesting SSd can be a potent agent for CRPC therapy. PMID:27155154

  11. Long-Term PSA Control with Repeated Stereotactic Body Radiotherapy in a Patient with Oligometastatic Castration-Resistant Prostate Cancer.

    PubMed

    Pasqualetti, Francesco; Cocuzza, Paola; Coraggio, Gabriele; Ferrazza, Patrizia; Derosa, Lisa; Galli, Luca; Pasqualetti, Giuseppe; Locantore, Luisa; Boni, Roberto; Fabrini, Maria G; Erba, Paola A

    2016-01-01

    Prostate cancer (PCa) is one of the most common malignancies and main causes of cancer death in Western countries. In the presence of metastatic disease, systemic treatment remains the main clinical option. However, since the introduction of highly sensitive imaging techniques, a new clinical 'entity' of metastatic patients with a limited number of lesions has been defined: oligometastatic patients. In this patient group, the use of stereotactic body radiotherapy (SBRT) or other local therapies against all active sites of disease revealed by 18F-choline positron emission tomography/computed tomography (PET/CT) could achieve sufficient prostate-specific antigen (PSA) control. However, a clear benefit of this procedure in terms of significant endpoints is yet to be demonstrated. This case report describes our experience with treating a castration-resistant PCa patient with 18F-choline PET/CT-guided SBRT. Because of the occurrence of 5 metachronous lesions over 4 years, the pattern of recurrence was defined by the local multidisciplinary team as oligometastatic disease, and the patient was treated with 5 courses of SBRT which yielded good PSA control. He started systemic therapy with abiraterone acetate almost 5 years after the diagnosis of recurrent PCa. PMID:27160394

  12. Improvement in survival and quality of life with new therapeutic agents in metastatic castration-resistant prostate cancer: comparison among the results.

    PubMed

    Recine, F; Ceresoli, G L; Baciarello, G; Cerbone, L; Calabrò, F

    2015-12-01

    Androgen deprivation therapy is the mainstay of treatment for men affected by metastatic prostate cancer (PC). Unfortunately, nearly all patient will become resistant to the initial hormonal approach, developing a metastatic castration-resistant prostate cancer (mCRPC). For many years, chemotherapy with docetaxel has been the only established standard of care for men with mCRPC. Recent developments in the knowledge of the disease biology have shown that during the progression to the castrate status PC remains dependent on androgens and androgen receptor (AR) pathway. As a consequence, new agents like abiraterone acetate and enzalutamide have been rapidly developed and approved for clinical use. Other drugs with different mechanisms of action, such as sipuleucel-T, cabazitaxel, and radium-223 have shown to improve overall survival, symptom control and quality of life of mCRPC patients. However, the optimal sequencing and combination of these treatments are not defined yet. Studies on biomarkers for treatment selection, such as AR splice variants, are promising, but the initial data still need prospective validation on large patient series. PMID:26337241

  13. SU-D-303-01: Spatial Distribution of Bone Metastases In Metastatic Castrate-Resistant Prostate Cancer

    SciTech Connect

    Perk, T; Bradshaw, T; Harmon, S; Perlman, S; Liu, G; Jeraj, R

    2015-06-15

    Purpose: Identification of metastatic bone lesions is critical in prostate cancer, where treatments may be more effective in patients with fewer lesions. This study aims characterize the distribution and spread of bone lesions and create a probability map of metastatic spread in bone. Methods: Fifty-five metastatic castrate-resistant prostate cancer patients received up to 3 whole-body [F-18]NaF PET/CT scans. Lesions were identified by physician on PET/CT and contoured using a threshold of SUV>15. An atlas-based segmentation method was used to create CT regions, which determined skeletal location of lesions. Patients were divided into 3 groups with low (N<40), medium (40100) numbers of lesions. A combination of articulated and deformable registrations was used to register the skeletal segments and lesions of each patient to a single skeleton. All the lesion data was then combined to make a probability map. Results: A total of 4038 metastatic lesions (mean 74, range 2–304) were identified. Skeletal regions with highest occurrence of lesions included ribs, thoracic spine, and pelvis with 21%, 19%, and 15% of the total number lesions and 8%, 18%, and 31 % of the total lesion volume, respectively. Interestingly, patients with fewer lesions were found to have a lower proportion of lesions in the ribs (9% in low vs. 27% in high number of lesions). Additionally, the probability map showed specific areas in the spine and pelvis where over 75% of patients had metastases, and other areas in the skeleton with a less than 2% of metastases. Conclusion: We identified skeletal regions with higher incidence of metastases and specific sub-regions in the skeleton that had high or low probability of occurrence of metastases. Additionally, we found that metastatic lesions in the ribs and skull occur more commonly in advanced disease. These results may have future applications in computer-aided diagnosis. Funding from the Prostate Cancer Foundation.

  14. Molecular analysis of CD133-positive circulating tumor cells from patients with metastatic castration-resistant prostate cancer

    PubMed Central

    Reyes, Edwin E; Gillard, Marc; Duggan, Ryan; Wroblewski, Kristen; Kregel, Steven; Isikbay, Masis; Kach, Jacob; Brechka, Hannah; Weele, David J Vander; Szmulewitz, Russell Z; Griend, Donald J Vander

    2015-01-01

    The function and clinical utility of stem cell markers in metastatic castration-resistant prostate cancer (mCRPC) remains unresolved, and their expression may confer important therapeutic opportunities for staging and therapy. In the adult human prostate, CD133 (PROM1) expression identifies infrequent prostate epithelial progenitor cells and putative cancer stem cells. Previous work demonstrated an association with CD133 and cancer cell proliferation using in vitro model systems. The primary objective here was to investigate the expression of CD133 in circulating tumor cells (CTCs) from patients with mCRPC and to test the hypothesis that patients with mCRPC had CD133-positive CTCs associated with increased cell proliferation, changes in the androgen receptor (AR) protein expression, or AR nuclear co-localization. We utilized ImageStreamX technology, which combines flow cytometry and fluorescence microscopy, to capture and analyze CD45-negative/EpCAM-positive CTCs for CD133, Ki-67, and AR. All patient samples (20/20) contained CD133-positive populations of CTCs, and on average 50.9 ± 28.2% (range of 18.2% to 100%) of CTCs were CD133-positive. CD133-positive CTCs have increased Ki-67 protein expression compared to CD133-negative CTCs, implying that CD133-positive CTCs may have greater proliferative potential when compared to their CD133-negative counterparts. CD133-positive and CD133-negative CTCs have similar levels of AR protein expression and cellular co-localization with nuclear markers, implying that CD133 expression is independent of AR pathway activity and an AR-independent marker of mCRPC proliferation. These studies demonstrate the presence of CD133-positive populations in CTCs from mCRPC with increased proliferative potential. PMID:26753099

  15. MED15, encoding a subunit of the mediator complex, is overexpressed at high frequency in castration-resistant prostate cancer.

    PubMed

    Shaikhibrahim, Zaki; Menon, Roopika; Braun, Martin; Offermann, Anne; Queisser, Angela; Boehm, Diana; Vogel, Wenzel; Rüenauver, Kerstin; Ruiz, Christian; Zellweger, Tobias; Svensson, Maria; Andren, Ove; Kristiansen, Glen; Wernert, Nicolas; Bubendorf, Lukas; Kirfel, Jutta; Biskup, Saskia; Perner, Sven

    2014-07-01

    The mediator complex is an evolutionary conserved key regulator of transcription of protein-coding genes and an integrative hub for diverse signaling pathways. In this study, we investigated whether the mediator subunit MED15 is implicated in castration-resistant prostate cancer (CRPC). MED15 expression and copy number/rearrangement status were assessed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively on 718 prostate cancer (PCa) specimens and sequenced by Sanger on a subset. Furthermore, SMAD3 phosphorylation, androgen receptor (AR) and proliferation markers were evaluated by IHC. In PCa cells, siRNA/shRNA knockdown of MED15 was followed by proliferation assays with/without dihydrotestosterone (DHT), and treatments with recombinant TGF-β3. Our results show that MED15 is overexpressed in 76% of distant metastatic CRPC (CRPC(MET) ) and 70% of local-recurrent CRPC (CRPC(LOC) ), in contrast to low frequencies in androgen-sensitive PCa, and no expression in benign prostatic tissue. Furthermore, MED15 overexpression correlates with worse clinical outcome thus defining a highly lethal phenotype. Moreover, TGF-β signaling activation associates with MED15 overexpression in PCa tissues, and leads to increased expression of MED15 in PCa cells. MED15 knockdown effects phosphorylation and shuttling of p-SMAD3 to the nucleus as well as TGF-β-enhanced proliferation. In PCa tissues, MED15 overexpression associates with AR overexpression/amplification and correlates with high proliferative activity. MED15 knockdown decreases both androgen-dependent and -independent proliferation in PCa cells. Taken together, these findings implicate MED15 in CRPC, and as MED15 is evolutionary conserved, it is likely to emerge as a lethal phenotype in other therapeutic-resistant diseases, and not restricted to our disease model. PMID:24374838

  16. Clinical variables associated with PSA response to abiraterone acetate in patients with metastatic castration-resistant prostate cancer

    PubMed Central

    Leibowitz-Amit, R.; Templeton, A. J.; Omlin, A.; Pezaro, C.; Atenafu, E. G.; Keizman, D.; Vera-Badillo, F.; Seah, J.-A.; Attard, G.; Knox, J. J.; Sridhar, S. S.; Tannock, I. F.; de Bono, J. S.; Joshua, A. M.

    2014-01-01

    Background Abiraterone acetate (abiraterone) prolongs overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC). This study's objective was to retrospectively identify factors associated with prostate-specific antigen (PSA) response to abiraterone and validate them in an independent cohort. We hypothesized that the neutrophil/lymphocyte ratio (NLR), thought to be an indirect manifestation of tumor-promoting inflammation, may be associated with response to abiraterone. Patients and methods All patients receiving abiraterone at the Princess Margaret (PM) Cancer Centre up to March 2013 were reviewed. The primary end point was confirmed PSA response defined as PSA decline ≥50% below baseline maintained for ≥3 weeks. Potential factors associated with PSA response were analyzed using univariate and multivariable analyses to generate a score, which was then evaluated in an independent cohort from Royal Marsden (RM) NHS foundation. Results A confirmed PSA response was observed in 44 out of 108 assessable patients (41%, 95% confidence interval 31%–50%). In univariate analysis, lower pre-abiraterone baseline levels of lactate dehydrogenase, an NLR ≤ 5 and restricted metastatic spread to either bone or lymph nodes were each associated with PSA response. In multivariable analysis, only low NLR and restricted metastatic spread remained statistically significant. A score derived as the sum of these two categorical variables was associated with response to abiraterone (P = 0.007). Logistic regression analysis on an independent validation cohort of 245 patients verified that this score was associated with response to abiraterone (P = 0.003). It was also associated with OS in an exploratory analysis. Conclusions A composite score of baseline NLR and extent of metastatic spread is associated with PSA response to abiraterone and OS. Our data may help understand the role of systemic inflammation in mCRPC and warrant further research. PMID

  17. The use of circulating tumor cells in guiding treatment decisions for patients with metastatic castration-resistant prostate cancer.

    PubMed

    Onstenk, Wendy; de Klaver, Willemijn; de Wit, Ronald; Lolkema, Martijn; Foekens, John; Sleijfer, Stefan

    2016-05-01

    The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) has drastically changed over the past decade with the advent of several new anti-tumor agents. Oncologists increasingly face dilemmas concerning the best treatment sequence for individual patients since most of the novel compounds have been investigated and subsequently positioned either pre- or post-docetaxel. A currently unmet need exists for biomarkers able to guide treatment decisions and to capture treatment resistance at an early stage thereby allowing for an early change to an alternative strategy. Circulating tumor cells (CTCs) have in this context intensively been investigated over the last years. The CTC count, as determined by the CellSearch System (Janssen Diagnostics LLC, Raritan, NJ), is a strong, independent prognostic factor for overall survival in patients with mCRPC at various time points during treatment and, as an early response marker, outperforms traditional response evaluations using serum prostate specific antigen (PSA) levels, scintigraphy as well as radiography. The focus of research is now shifting toward the predictive value of CTCs and the use of the characterization of CTCs to guide the selection of treatments with the highest chance of success for individual patients. Recently, the presence of the androgen receptor splice variant 7 (AR-V7) has been shown to be a promising predictive factor. In this review, we have explored the clinical value of the enumeration and characterization of CTCs for the treatment of mCRPC and have put the results obtained from recent studies investigating the prognostic and predictive value of CTCs into clinical perspective. PMID:27107266

  18. Whole blood defensin mRNA expression is a predictive biomarker of docetaxel response in castration-resistant prostate cancer

    PubMed Central

    Kohli, Manish; Young, Charles YF; Tindall, Donald J; Nandy, Debashis; McKenzie, Kyle M; Bevan, Graham H; Donkena, Krishna Vanaja

    2015-01-01

    This study tested the potential of circulating RNA-based signals as predictive biomarkers for docetaxel response in patients with metastatic castration-resistant prostate cancer (CRPC). RNA was analyzed in blood from six CRPC patients by whole-transcriptome sequencing (total RNA-sequencing) before and after docetaxel treatment using the Illumina’s HiSeq platform. Targeted RNA capture and sequencing was performed in an independent cohort of ten patients with CRPC matching the discovery cohort to confirm differential expression of the genes. Response to docetaxel was defined on the basis of prostate-specific antigen levels and imaging criteria. Two-way analysis of variance was used to compare differential gene expression in patients classified as responders versus nonresponders before and after docetaxel treatment. Thirty-four genes with two-fold differentially expressed transcripts in responders versus nonresponders were selected from total RNA-sequencing for further validation. Targeted RNA capture and sequencing showed that 13/34 genes were differentially expressed in responders. Alpha defensin genes DEFA1, DEFA1B, and DEFA3 exhibited significantly higher expression in responder patients compared with nonresponder patients before administration of chemotherapy (fold change >2.5). In addition, post-docetaxel treatment significantly increased transcript levels of these defensin genes in responders (fold change >2.8). Our results reveal that patients with higher defensin RNA transcripts in blood respond well to docetaxel therapy. We suggest that monitoring DEFA1, DEFA1B, and DEFA3 RNA transcripts in blood prior to treatment will be helpful to determine which patients are better candidates to receive docetaxel chemotherapy. PMID:26261420

  19. Whole blood defensin mRNA expression is a predictive biomarker of docetaxel response in castration-resistant prostate cancer.

    PubMed

    Kohli, Manish; Young, Charles Yf; Tindall, Donald J; Nandy, Debashis; McKenzie, Kyle M; Bevan, Graham H; Donkena, Krishna Vanaja

    2015-01-01

    This study tested the potential of circulating RNA-based signals as predictive biomarkers for docetaxel response in patients with metastatic castration-resistant prostate cancer (CRPC). RNA was analyzed in blood from six CRPC patients by whole-transcriptome sequencing (total RNA-sequencing) before and after docetaxel treatment using the Illumina's HiSeq platform. Targeted RNA capture and sequencing was performed in an independent cohort of ten patients with CRPC matching the discovery cohort to confirm differential expression of the genes. Response to docetaxel was defined on the basis of prostate-specific antigen levels and imaging criteria. Two-way analysis of variance was used to compare differential gene expression in patients classified as responders versus nonresponders before and after docetaxel treatment. Thirty-four genes with two-fold differentially expressed transcripts in responders versus nonresponders were selected from total RNA-sequencing for further validation. Targeted RNA capture and sequencing showed that 13/34 genes were differentially expressed in responders. Alpha defensin genes DEFA1, DEFA1B, and DEFA3 exhibited significantly higher expression in responder patients compared with nonresponder patients before administration of chemotherapy (fold change >2.5). In addition, post-docetaxel treatment significantly increased transcript levels of these defensin genes in responders (fold change >2.8). Our results reveal that patients with higher defensin RNA transcripts in blood respond well to docetaxel therapy. We suggest that monitoring DEFA1, DEFA1B, and DEFA3 RNA transcripts in blood prior to treatment will be helpful to determine which patients are better candidates to receive docetaxel chemotherapy. PMID:26261420

  20. PTEN loss in circulating tumour cells correlates with PTEN loss in fresh tumour tissue from castration-resistant prostate cancer patients

    PubMed Central

    Punnoose, Elizabeth A; Ferraldeschi, Roberta; Szafer-Glusman, Edith; Tucker, Eric K; Mohan, Sankar; Flohr, Penelope; Riisnaes, Ruth; Miranda, Susana; Figueiredo, Ines; Rodrigues, Daniel Nava; Omlin, Aurelius; Pezaro, Carmel; Zhu, Jin; Amler, Lukas; Patel, Premal; Yan, Yibing; Bales, Natalee; Werner, Shannon L; Louw, Jessica; Pandita, Ajay; Marrinucci, Dena; Attard, Gerhardt; de Bono, Johann

    2015-01-01

    Background: PTEN gene loss occurs frequently in castration-resistant prostate cancer (CRPC) and may drive progression through activation of the PI3K/AKT pathway. Here, we developed a novel CTC-based assay to determine PTEN status and examined the correlation between PTEN status in CTCs and matched tumour tissue samples. Methods: PTEN gene status in CTCs was evaluated on an enrichment-free platform (Epic Sciences) by fluorescence in situ hybridisation (FISH). PTEN status in archival and fresh tumour tissue was evaluated by FISH and immunohistochemistry. Results: Peripheral blood was collected from 76 patients. Matched archival and fresh cancer tissue was available for 48 patients. PTEN gene status detected in CTCs was concordant with PTEN status in matched fresh tissues and archival tissue in 32 of 38 patients (84%) and 24 of 39 patients (62%), respectively. CTC counts were prognostic (continuous, P=0.001). PTEN loss in CTCs associated with worse survival in univariate analysis (HR 2.05; 95% CI 1.17–3.62; P=0.01) and with high lactate dehydrogenase (LDH) in metastatic CRPC patients. Conclusions: Our results illustrate the potential use of CTCs as a non-invasive, real-time liquid biopsy to determine PTEN gene status. The prognostic and predictive value of PTEN in CTCs warrants investigation in CRPC clinical trials of PI3K/AKT-targeted therapies. PMID:26379078

  1. Common Genetic Variation in CYP17A1 and Response to Abiraterone Acetate in Patients with Metastatic Castration-Resistant Prostate Cancer

    PubMed Central

    Binder, Moritz; Zhang, Ben Y.; Hillman, David W.; Kohli, Rhea; Kohli, Tanvi; Lee, Adam; Kohli, Manish

    2016-01-01

    Treatment with abiraterone acetate and prednisone (AA/P) prolongs survival in metastatic castration-resistant prostate cancer (mCRPC) patients. We evaluated the genetic variation in CYP17A1 as predictive of response to AA/P. A prospective collection of germline DNA prior to AA/P initiation and follow-up of a mCRPC cohort was performed. Five common single-nucleotide polymorphisms (SNPs) in CYP17A1 identified using a haplotype-based tagging algorithm were genotyped. Clinical outcomes included biochemical response and time to biochemical progression on AA/P. Logistic regression was used to assess the association between tag SNPs and biochemical response. Proportional hazards regression was used to assess the association between tag SNPs and time to biochemical progression. Odds or hazard ratio per minor allele were estimated and p-values below 0.05 were considered statistically significant. Germline DNA was successfully genotyped for four tag SNPs in 87 patients. The median age was 73 years (54–90); the median prostate-specific antigen was 66 ng/dL (0.1–99.9). A single SNP, rs2486758, was associated with lower odds of experiencing a biochemical response (Odds ratio 0.22, 95% confidence interval 0.07–0.63, p = 0.005) and a shorter time to biochemical progression (Hazard ratio 2.23, 95% confidence interval 1.39–3.56, p < 0.001). This tag SNP located in the promoter region of CYP17A1 will need further validation as a predictive biomarker for AA/P therapy. PMID:27409606

  2. Common Genetic Variation in CYP17A1 and Response to Abiraterone Acetate in Patients with Metastatic Castration-Resistant Prostate Cancer.

    PubMed

    Binder, Moritz; Zhang, Ben Y; Hillman, David W; Kohli, Rhea; Kohli, Tanvi; Lee, Adam; Kohli, Manish

    2016-01-01

    Treatment with abiraterone acetate and prednisone (AA/P) prolongs survival in metastatic castration-resistant prostate cancer (mCRPC) patients. We evaluated the genetic variation in CYP17A1 as predictive of response to AA/P. A prospective collection of germline DNA prior to AA/P initiation and follow-up of a mCRPC cohort was performed. Five common single-nucleotide polymorphisms (SNPs) in CYP17A1 identified using a haplotype-based tagging algorithm were genotyped. Clinical outcomes included biochemical response and time to biochemical progression on AA/P. Logistic regression was used to assess the association between tag SNPs and biochemical response. Proportional hazards regression was used to assess the association between tag SNPs and time to biochemical progression. Odds or hazard ratio per minor allele were estimated and p-values below 0.05 were considered statistically significant. Germline DNA was successfully genotyped for four tag SNPs in 87 patients. The median age was 73 years (54-90); the median prostate-specific antigen was 66 ng/dL (0.1-99.9). A single SNP, rs2486758, was associated with lower odds of experiencing a biochemical response (Odds ratio 0.22, 95% confidence interval 0.07-0.63, p = 0.005) and a shorter time to biochemical progression (Hazard ratio 2.23, 95% confidence interval 1.39-3.56, p < 0.001). This tag SNP located in the promoter region of CYP17A1 will need further validation as a predictive biomarker for AA/P therapy. PMID:27409606

  3. Hypercholesterolemia Is Associated with a Shorter Time to Castration-Resistant Prostate Cancer in Patients Who Have Undergone Androgen Deprivation Therapy

    PubMed Central

    Jeon, Jong Chul; Park, Jaeyoung; Park, Sungchan; Moon, Kyung Hyun; Cheon, Sang Hyeon

    2016-01-01

    Purpose The goal of this study was to investigate the association between hypercholesterolemia and the time required for progression to castration-resistant prostate cancer (CRPC) in patients who have undergone androgen deprivation therapy (ADT). Materials and Methods Data from 154 patients with prostate cancer between 2005 and 2012 were reviewed retrospectively. ADT was employed as a treatment modality for these patients either due to multiple bone metastases at the time of diagnosis or due to old age in combination with other morbidities. Serum cholesterol levels and statin use were reviewed. We analyzed the factors associated with the development of CRPC after ADT treatment. The mean follow-up period was 34.8 months. Results The mean age of the patients was 71.3 years old and their mean prostate-specific antigen level was 141.8±212.6 ng/mL. Their mean cholesterol level was 175.9±37.7 mg/dL, and 14 patients (9.1%) were statin users. CRPC developed in 44 patients (28.6%), and the mean duration from ADT treatment to CRPC was 24.1 months. In a multivariate analysis, hypercholesterolemia was associated with the development of CRPC (hazard ratio [HR]=1.017, p<0.001), depending on clinical T stage (p=0.005) and the presence of bone metastasis (p<0.001). A subanalysis showed that hypercholesterolemia was associated with the development of CRPC in patients with bone metastasis (HR=1.032, p<0.001), but not in patients without bone metastasis. Conclusions Hypercholesterolemia may be associated with the development of CRPC after ADT in patients with bone metastasis. Further studies with longer follow-up periods and larger samples are needed to validate this finding. PMID:27169126

  4. Therapeutic Algorithm Guided by Sequential 11C-Choline PET/CT in a Patient With Metastatic Castration-Resistant Prostate Cancer.

    PubMed

    Garcia Garzon, J R; Bassa, Pere; Soler, Marina; Moragas, Merce; Llinares, Elena; Riera, Eduard

    2015-07-01

    Antiandrogen therapy alone or combined with radical therapy is the first choice in diagnosis and recurrence of patients with metastatic prostate cancer. However, patients on androgen deprivation frequently show treatment resistance. In recent years, new treatments for metastatic castration-resistant prostate cancer have been developed. Clinical studies with docetaxel have shown its usefulness for first-line therapy, and different therapeutic algorithms with second-line drugs like abiraterone or cabazitaxel have also been proposed. Sequential metabolic study with PET/CT imaging with ¹¹C-choline may be important for assessing the right moment for administration each one of the therapeutic options. PMID:25742237

  5. Uroncor consensus statement: Management of biochemical recurrence after radical radiotherapy for prostate cancer: From biochemical failure to castration resistance.

    PubMed

    López Torrecilla, José; Hervás, Asunción; Zapatero, Almudena; Gómez Caamaño, Antonio; Macías, Victor; Herruzo, Ismael; Maldonado, Xavier; Gómez Iturriaga, Alfonso; Casas, Francesc; González San Segundo, Carmen

    2015-01-01

    Management of patients who experience biochemical failure after radical radiotherapy with or without hormonal therapy is highly challenging. The clinician must not only choose the type of treatment, but also the timing and optimal sequence of treatment administration. When biochemical failure occurs, numerous treatment scenarios are possible, thus making it more difficult to select the optimal approach. Moreover, rapid and ongoing advances in treatment options require that physicians make decisions that could impact both survival and quality of life. The aim of the present consensus statement, developed by the Urological Tumour Working Group (URONCOR) of the Spanish Society of Radiation Oncology (SEOR), is to provide cancer specialists with the latest, evidence-based information needed to make the best decisions for the patient under all possible treatment scenarios. The structure of this consensus statement follows the typical development of disease progression after biochemical failure, with the most appropriate treatment recommendations given for each stage. The consensus statement is organized into three separate chapters, as follows: biochemical failure with or without local recurrence and/or metastasis; progression after salvage therapy; and treatment of castration-resistant patients. PMID:26109913

  6. Significant and Sustained Antitumor Activity in Post-Docetaxel, Castration-Resistant Prostate Cancer With the CYP17 Inhibitor Abiraterone Acetate

    PubMed Central

    Reid, Alison H.M.; Attard, Gerhardt; Danila, Daniel C.; Oommen, Nikhil Babu; Olmos, David; Fong, Peter C.; Molife, L. Rhoda; Hunt, Joanne; Messiou, Christina; Parker, Christopher; Dearnaley, David; Swennenhuis, Joost F.; Terstappen, Leon W.M.M.; Lee, Gloria; Kheoh, Thian; Molina, Arturo; Ryan, Charles J.; Small, Eric; Scher, Howard I.; de Bono, Johann S.

    2010-01-01

    Purpose The principal objective of this trial was to evaluate the antitumor activity of abiraterone acetate, an oral, specific, irreversible inhibitor of CYP17 in docetaxel-treated patients with castration-resistant prostate cancer (CRPC). Patients and Methods In this multicenter, two-stage, phase II study, abiraterone acetate 1,000 mg was administered once daily continuously. The primary end point was achievement of a prostate-specific antigen (PSA) decline of ≥ 50% in at least seven of 35 patients. Per an attained phase II design, more than 35 patients could be enrolled if the primary end point was met. Secondary objectives included: PSA declines of ≥ 30% and ≥ 90%; rate of RECIST (Response Evaluation Criteria in Solid Tumors) responses and duration on study; time to PSA progression; safety and tolerability; and circulating tumor cell (CTC) enumeration. Results Docetaxel-treated patients with CRPC (N = 47) were enrolled. PSA declines of ≥ 30%, ≥ 50% and ≥ 90% were seen in 68% (32 of 47), 51% (24 of 47), and 15% (seven of 47) of patients, respectively. Partial responses (by RECIST) were reported in eight (27%) of 30 patients with measurable disease. Median time to PSA progression was 169 days (95% CI, 113 to 281 days). The median number of weeks on study was 24, and 12 (25.5%) of 47 patients remained on study ≥ 48 weeks. CTCs were enumerated in 34 patients; 27 (79%) of 34 patients had at least five CTCs at baseline. Eleven (41%) of 27 patients had a decline from at least five to less than 5 CTCs, and 18 (67%) of 27 had a ≥ 30% decline in CTCs after starting treatment with abiraterone acetate. Abiraterone acetate was well tolerated. Conclusion Abiraterone acetate has significant antitumor activity in post-docetaxel patients with CRPC. Randomized, phase III trials of abiraterone acetate are underway to define the future role of this agent. PMID:20159823

  7. Phase 1/2 study of orteronel (TAK-700), an investigational 17,20-lyase inhibitor, with docetaxel–prednisone in metastatic castration-resistant prostate cancer

    PubMed Central

    Gandhi, Jitendra G.; Clark, William R.; Heath, Elisabeth; Lin, Jianqing; Oh, William K.; Agus, David B.; Carthon, Bradley; Moran, Susan; Kong, Ning; Suri, Ajit; Bargfrede, Michael; Liu, Glenn

    2015-01-01

    Summary Background Docetaxel–prednisone (DP) is an approved therapy for metastatic castration-resistant prostate cancer (mCRPC). Orteronel (TAK-700) is an investigational, selective, non-steroidal inhibitor of 17,20-lyase, a key enzyme in androgenic hormone production. This phase 1/2 study evaluated orteronel plus DP in mCRPC patients. Methods Adult men with chemotherapy-naïve mCRPC, serum prostate-specific antigen (PSA) ≥5 ng/mL, and serum testosterone <50 ng/dL received oral orteronel 200 or 400 mg twice-daily (BID) in phase 1 to determine the recommended dose for phase 2, plus intravenous docetaxel 75 mg/m2 every 3 weeks, and oral prednisone 5 mg BID. Phase 2 objectives included safety, pharmacokinetics, and efficacy. Results In phase 1 (n=6, orteronel 200 mg; n=8, orteronel 400 mg), there was one dose-limiting toxicity of grade 3 febrile neutropenia at 400 mg BID. This dose was evaluated further in phase 2 (n=23). After 4 cycles, 68, 59, and 23 % of patients achieved ≥30, ≥50, and ≥90 % PSA reductions, respectively; median best PSA response was −77 %. Seven of 10 (70 %) RECIST-evaluable patients achieved objective partial responses. Median time to PSA progression and radio-graphic disease progression was 6.7 and 12.9 months, respectively. Dehydroepiandrosterone-sulfate (DHEA-S) and testosterone levels were rapidly and durably reduced. Common adverse events were fatigue (78 %), alopecia (61 %), diarrhea (48 %), nausea (43 %), dysgeusia (39 %), and neutropenia (39 %). Orteronel and docetaxel pharmacokinetics were similar alone and in combination. Conclusions Orteronel plus DP was tolerable, with substantial reductions in PSA, DHEA-S, and testosterone levels, and evidence for measurable disease responses. PMID:25556680

  8. Impact of enzalutamide on quality of life in men with metastatic castration-resistant prostate cancer after chemotherapy: additional analyses from the AFFIRM randomized clinical trial

    PubMed Central

    Cella, D.; Ivanescu, C.; Holmstrom, S.; Bui, C. N.; Spalding, J.; Fizazi, K.

    2015-01-01

    Background To present longitudinal changes in Functional Assessment of Cancer Therapy-Prostate (FACT-P) scores during 25-week treatment with enzalutamide or placebo in men with progressive metastatic castration-resistant prostate cancer (mCRPC) after chemotherapy in the AFFIRM trial. Patients and methods Patients were randomly assigned to enzalutamide 160 mg/day or placebo. FACT-P was completed before randomization, at weeks 13, 17, 21, and 25, and every 12 weeks thereafter while on study treatment. Longitudinal changes in FACT-P scores from baseline to 25 weeks were analyzed using a mixed effects model for repeated measures (MMRM), with a pattern mixture model (PMM) applied as secondary analysis to address non-ignorable missing data. Cumulative distribution function (CDF) plots were generated and different methodological approaches and models for handling missing data were applied. Due to the exploratory nature of the analyses, adjustments for multiple comparisons were not made. AFFIRM is registered with ClinicalTrials.gov, number NCT00974311. Results The intention-to-treat FACT-P population included 938 patients (enzalutamide, n = 674; placebo n = 264) with evaluable FACT-P assessments at baseline and ≥1 post-baseline assessment. After 25 weeks, the mean FACT-P total score decreased by 1.52 points with enzalutamide compared with 13.73 points with placebo (P < 0.001). In addition, significant treatment differences at week 25 favoring enzalutamide were evident for all FACT-P subscales and indices, whether analyzed by MMRM or PMM. CDF plots revealed differences favoring enzalutamide compared with placebo across the full range of possible response levels for FACT-P total and all disease- and symptom-specific subscales/indices. Conclusion In men with progressive mCRPC after docetaxel-based chemotherapy, enzalutamide is superior to placebo in health-related quality-of-life outcomes, regardless of analysis model or threshold selected for meaningful response. Clinical

  9. Evolving Role of Bone Biomarkers in Castration-Resistant Prostate Cancer1

    PubMed Central

    Brown, Janet E; Sim, Sheryl

    2010-01-01

    The preferential metastasis of prostate cancer cells to bone disrupts the process of bone remodeling and results in lesions that cause significant pain and patient morbidity. Although prostate-specific antigen (PSA) is an established biomarker in prostate cancer, it provides only limited information relating to bone metastases and the treatment of metastatic bone disease with bisphosphonates or novel noncytotoxic targeted or biological agents that may provide clinical benefits without affecting PSA levels. As bone metastases develop, factors derived from bone metabolism are released into blood and urine, including N- and C-terminal peptide fragments of type 1 collagen and bone-specific alkaline phosphatase, which represent potentially useful biomarkers for monitoring metastatic bone disease. A number of clinical trials have investigated these bone biomarkers with respect to their diagnostic, prognostic, and predictive values. Results suggest that higher levels of bone biomarkers are associated with an increased risk of skeletal-related events and/or death. As a result of these findings, bone biomarkers are now being increasingly used as study end points, particularly in studies investigating novel agents with putative bone effects. Data from prospective clinical trials are needed to validate the use of bone biomarkers and to confirm that marker levels provide additional information beyond traditional methods of response evaluation for patients with metastatic prostate cancer. PMID:20824045

  10. Food effects on abiraterone pharmacokinetics in healthy subjects and patients with metastatic castration-resistant prostate cancer.

    PubMed

    Chi, Kim N; Spratlin, Jennifer; Kollmannsberger, Christian; North, Scott; Pankras, Catherine; Gonzalez, Martha; Bernard, Apexa; Stieltjes, Hans; Peng, Lixian; Jiao, James; Acharya, Milin; Kheoh, Thian; Griffin, Thomas W; Yu, Margaret K; Chien, Caly; Tran, Nam Phuong

    2015-12-01

    Food effect on abiraterone pharmacokinetics and safety on abiraterone acetate coadministration with low-fat or high-fat meals was examined in healthy subjects and metastatic castration-resistant prostate cancer (mCRPC) patients. Healthy subjects (n = 36) were randomized to abiraterone acetate (single dose, 1000 mg) + low-fat meal, + high-fat meal, and fasted state. mCRPC patients received repeated doses (abiraterone acetate 1000 mg + 5 mg prednisone twice daily; days 1-7) in a modified fasting state followed by abiraterone acetate plus prednisone within 0.5 hours post-low-fat (n = 6) or high-fat meal (n = 18; days 8-14). In healthy subjects, geometric mean (GM) abiraterone area under plasma concentration-time curve (AUC) increased ∼5- and ∼10-fold, respectively, with low-fat and high-fat meals versus fasted state (GM [coefficient of variation], 1942 [48] and 4077 [37] ng · h/mL vs 421 [67] ng · h/mL, respectively). In mCRPC patients, abiraterone AUC was ∼2-fold higher with a high-fat meal and similar with a low-fat meal versus modified fasting state (GM [coefficient of variation]: 1992 [34] vs 973 [58] ng · h/mL and 1264 [65] vs 1185 [90] ng · h/mL, respectively). Adverse events (all grade ≤ 3) were similar, with high-fat/low-fat meals or fasted/modified fasting state. Short-term dosing with food did not alter abiraterone acetate safety. PMID:26096139

  11. Radium-223 chloride: a potential new treatment for castration-resistant prostate cancer patients with metastatic bone disease

    PubMed Central

    Harrison, Michael R; Wong, Terence Z; Armstrong, Andrew J; George, Daniel J

    2013-01-01

    Background Radium-223 chloride (223Ra; Alpharadin) is an alpha-emitting radioisotope that targets areas of osteoblastic metastasis and is excreted by the small intestine. When compared with beta-emitters (eg, strontium-89, samarium-153), 223Ra delivers a high quantity of energy per track length with short tissue penetration. Objective This review describes the mechanism, radiobiology, and preclinical development of 223Ra and discusses the clinical data currently available regarding its safety and efficacy profile. Methods Data from clinical trials including abstracts were collected and reviewed using the PubMed Database, as well as the American Society of Clinical Oncology abstract database. Conclusion Current bone-targeted therapies fall into two main categories: antiresorptive agents (eg, zoledronic acid, denosumab), which have been shown to delay skeletal-related events, and radiopharmaceuticals (eg, samarium-153), which may have a role in pain palliation. Historically, neither antiresorptive agents nor radiopharmaceuticals have shown definitive evidence of improved overall survival or other antitumor effects in metastatic castrate-resistant prostate cancer (mCRPC). Radiopharmaceuticals are limited by myelosuppresion, thrombocytopenia, and renal excretion. In a recently reported randomized Phase III trial in men with symptomatic bone-metastatic CRPC who had received or were ineligible for docetaxel chemotherapy, 223Ra treatment resulted in improved overall survival and delayed skeletal-related events. Toxicity consisted of minor gastrointestinal side effects and mild neutropenia and thrombocytopenia that were rarely severe. Pending regulatory approval, 223Ra may represent a unique and distinct option for an important subgroup of patients with mCRPC; future trials should address its use in combination or in sequence with existing and novel agents. PMID:23326203

  12. Epithelial mesenchymal-like transition occurs in a subset of cells in castration resistant prostate cancer bone metastases.

    PubMed

    Haider, Maahum; Zhang, Xiaotun; Coleman, Ilsa; Ericson, Nolan; True, Lawrence D; Lam, Hung-Ming; Brown, Lisha G; Ketchanji, Melanie; Nghiem, Belinda; Lakely, Bryce; Coleman, Roger; Montgomery, Bruce; Lange, Paul H; Roudier, Martine; Higano, Celestia S; Bielas, Jason H; Nelson, Peter S; Vessella, Robert L; Morrissey, Colm

    2016-03-01

    TGFβ is a known driver of epithelial-mesenchymal transition (EMT) which is associated with tumor aggressiveness and metastasis. However, EMT has not been fully explored in clinical specimens of castration-resistant prostate cancer (CRPC) metastases. To assess EMT in CRPC, gene expression analysis was performed on 149 visceral and bone metastases from 62 CRPC patients and immunohistochemical analysis was performed on 185 CRPC bone and visceral metastases from 42 CRPC patients. In addition, to assess the potential of metastases to seed further metastases the mitochondrial genome was sequenced at different metastatic sites in one patient. TGFβ was increased in bone versus visceral metastases. While primarily cytoplasmic; nuclear and cytoplasmic Twist were significantly higher in bone than in visceral metastases. Slug and Zeb1 were unchanged, with the exception of nuclear Zeb1 being significantly higher in visceral metastases. Importantly, nuclear Twist, Slug, and Zeb1 were only present in a subset of epithelial cells that had an EMT-like phenotype. Underscoring the relevance of EMT-like cells, mitochondrial sequencing revealed that metastases could seed additional metastases in the same patient. In conclusion, while TGFβ expression and EMT-associated protein expression is present in a considerable number of CRPC visceral and bone metastases, nuclear Twist, Slug, and Zeb1 localization and an EMT-like phenotype (elongated nuclei and cytoplasmic compartment) was only present in a small subset of CRPC bone metastases. Mitochondrial sequencing from different metastases in a CRPC patient provided evidence for the seeding of metastases from previously established metastases, highlighting the biological relevance of EMT-like behavior in CRPC metastases. PMID:26667932

  13. Anticancer activity of a novel selective CYP17A1 inhibitor in preclinical models of castrate-resistant prostate cancer.

    PubMed

    Toren, Paul J; Kim, Soojin; Pham, Steven; Mangalji, Azzra; Adomat, Hans; Guns, Emma S Tomlinson; Zoubeidi, Amina; Moore, William; Gleave, Martin E

    2015-01-01

    VT-464 is a novel, nonsteroidal, small-molecule CYP17A1 inhibitor with 17,20-lyase selectivity. This study evaluates the anticancer activity of VT-464 compared with abiraterone (ABI) in castrate-resistant prostate cancer cell lines and xenograft models that are enzalutamide (ENZ)-responsive (C4-2) or ENZ-resistant (MR49C, MR49F). In vitro, androgen receptor (AR) transactivation was assessed by probasin luciferase reporter, whereas AR and AR-regulated genes and steroidogenic pathway enzymes were assessed by Western blot and/or qRT-PCR. The MR49F xenograft model was used to compare effects of oral VT-464 treatment to vehicle and abiraterone acetate (AA). Steroid concentrations were measured using LC-MS chromatography. VT-464 demonstrated a greater decrease in AR transactivation compared with ABI in C4-2 and both ENZ-resistant cell lines. At the gene and protein level, VT-464 suppressed the AR axis to a greater extent compared with ABI. Gene transcripts StAR, CYP17A1, HSD17B3, and SRD5A1 increased following treatment with ABI and to a greater extent with VT-464. In vivo, intratumoral androgen levels were significantly lower after VT-464 or AA treatment compared with vehicle, with the greatest decrease seen with VT-464. Similarly, tumor growth inhibition and PSA decrease trends were greater with VT-464 than with AA. Finally, an AR-antagonist effect of VT-464 independent of CYP17A1 inhibition was observed using luciferase reporter assays, and a direct interaction was confirmed using an AR ligand binding domain biolayer interferometry. These preclinical results suggest greater suppression of the AR axis with VT-464 than ABI that is likely due to both superior selective suppression of androgen synthesis and AR antagonism. PMID:25351916

  14. Circulating Tumor Cell Biomarker Panel As an Individual-Level Surrogate for Survival in Metastatic Castration-Resistant Prostate Cancer

    PubMed Central

    Scher, Howard I.; Heller, Glenn; Molina, Arturo; Attard, Gerhardt; Danila, Daniel C.; Jia, Xiaoyu; Peng, Weimin; Sandhu, Shahneen K.; Olmos, David; Riisnaes, Ruth; McCormack, Robert; Burzykowski, Tomasz; Kheoh, Thian; Fleisher, Martin; Buyse, Marc; de Bono, Johann S.

    2015-01-01

    Purpose Trials in castration-resistant prostate cancer (CRPC) need new clinical end points that are valid surrogates for survival. We evaluated circulating tumor cell (CTC) enumeration as a surrogate outcome measure. Patients and Methods Examining CTCs alone and in combination with other biomarkers as a surrogate for overall survival was a secondary objective of COU-AA-301, a multinational, randomized, double-blind phase III trial of abiraterone acetate plus prednisone versus prednisone alone in patients with metastatic CRPC previously treated with docetaxel. The biomarkers were measured at baseline and 4, 8, and 12 weeks, with 12 weeks being the primary measure of interest. The Prentice criteria were applied to test candidate biomarkers as surrogates for overall survival at the individual-patient level. Results A biomarker panel using CTC count and lactate dehydrogenase (LDH) level was shown to satisfy the four Prentice criteria for individual-level surrogacy. Twelve-week surrogate biomarker data were available for 711 patients. The abiraterone acetate plus prednisone and prednisone-alone groups demonstrated a significant survival difference (P = .034); surrogate distribution at 12 weeks differed by treatment (P < .001); the discriminatory power of the surrogate to predict mortality was high (weighted c-index, 0.81); and adding the surrogate to the model eliminated the treatment effect on survival. Overall, 2-year survival of patients with CTCs < 5 (low risk) versus patients with CTCs ≥ 5 cells/7.5 mL of blood and LDH > 250 U/L (high risk) at 12 weeks was 46% and 2%, respectively. Conclusion A biomarker panel containing CTC number and LDH level was shown to be a surrogate for survival at the individual-patient level in this trial of abiraterone acetate plus prednisone versus prednisone alone for patients with metastatic CRPC. Additional trials are ongoing to validate the findings. PMID:25800753

  15. BAY 1024767 blocks androgen receptor mutants found in castration-resistant prostate cancer patients.

    PubMed

    Sugawara, Tatsuo; Lejeune, Pascale; Köhr, Silke; Neuhaus, Roland; Faus, Hortensia; Gelato, Kathy A; Busemann, Matthias; Cleve, Arwed; Lücking, Ulrich; von Nussbaum, Franz; Brands, Michael; Mumberg, Dominik; Jung, Klaus; Stephan, Carsten; Haendler, Bernard

    2016-02-01

    Androgen receptor (AR) mutations arise in patients developing resistance to hormone deprivation therapies. Here we describe BAY 1024767, a thiohydantoin derivative with strong antagonistic activity against nine AR variants with mutations located in the AR ligand-binding domain (LBD), and against wild-type AR. Antagonism was maintained, though reduced, at increased androgen levels. Anti-tumor efficacy was evidenced in vivo in the KuCaP-1 prostate cancer model which bears the W741C bicalutamide resistance mutation and in the syngeneic prostate cancer rat model Dunning R3327-G. The prevalence of six selected AR mutations was determined in plasma DNA originating from 100 resistant patients and found to be at least 12%. Altogether the results show BAY 1024767 to be a strong antagonist for several AR mutants linked to therapy resistance, which opens the door for next-generation compounds that can benefit patients based on their mutation profile. PMID:26760770

  16. BAY 1024767 blocks androgen receptor mutants found in castration-resistant prostate cancer patients

    PubMed Central

    Sugawara, Tatsuo; Lejeune, Pascale; Köhr, Silke; Neuhaus, Roland; Faus, Hortensia; Gelato, Kathy A.; Busemann, Matthias; Cleve, Arwed; Lücking, Ulrich; von Nussbaum, Franz; Brands, Michael; Mumberg, Dominik; Jung, Klaus; Stephan, Carsten; Haendler, Bernard

    2016-01-01

    Androgen receptor (AR) mutations arise in patients developing resistance to hormone deprivation therapies. Here we describe BAY 1024767, a thiohydantoin derivative with strong antagonistic activity against nine AR variants with mutations located in the AR ligand-binding domain (LBD), and against wild-type AR. Antagonism was maintained, though reduced, at increased androgen levels. Anti-tumor efficacy was evidenced in vivo in the KuCaP-1 prostate cancer model which bears the W741C bicalutamide resistance mutation and in the syngeneic prostate cancer rat model Dunning R3327-G. The prevalence of six selected AR mutations was determined in plasma DNA originating from 100 resistant patients and found to be at least 12%. Altogether the results show BAY 1024767 to be a strong antagonist for several AR mutants linked to therapy resistance, which opens the door for next-generation compounds that can benefit patients based on their mutation profile. PMID:26760770

  17. Exosomal miR-1290 and miR-375 as Prognostic Markers in Castration-resistant Prostate Cancer

    PubMed Central

    Huang, Xiaoyi; Yuan, Tiezheng; Liang, Meihua; Du, Meijun; Xia, Shu; Dittmar, Rachel; Wang, Dian; See, William; Costello, Brian A.; Quevedo, Fernando; Tan, Winston; Nandy, Debashis; Bevan, Graham H.; Longenbach, Sherri; Sun, Zhifu; Lu, Yan; Wang, Tao; Thibodeau, Stephen N.; Boardman, Lisa; Kohli, Manish; Wang, Liang

    2014-01-01

    Background Extracellular microRNAs (miRNAs) embedded in circulating exosomes may serves as prognostic biomarkers in cancer. Objective To identify and evaluate plasma exosomal miRNAs for prognosis in castration-resistant prostate cancer (CRPC). Design, setting, and participants RNA sequencing was performed to identify candidate exosomal miRNAs associated with overall survival in a screening cohort of 23 CRPC patients. Candidate miRNAs were further evaluated for prognosis using quantitative real-time polymerase chain reaction in a follow-up cohort of 100 CRPC patients. Outcome measurements and statistical analysis Cox regression and Kaplan-Meier survival analyses were used to evaluate survival association using candidate miRNAs along with clinical prognostic factors. Results and limitations RNA sequencing in screening cohort generated approximately 6.80 million mappable reads per patient. Of those with normalized read counts ≥5, 43% were mapped to miRNAs for a total of 375 known and 57 novel miRNAs. Cox regression analysis identified an association of miR-1290, -1246, and -375 with overall survival (false discover rate <0.05). Of those, higher levels of miR-1290 and -375 were significantly associated with poor overall survival (p < 0.004) in the follow-up cohort. Incorporation of miR-1290/-375 into putative clinical prognostic factors-based models in CRPC stage significantly improved predictive performance with a time-dependent area under the curve increase from 0.66 to 0.73 (p = 6.57 × 10−6). Conclusions Plasma exosomal miR-1290 and miR-375 are promising prognostic biomarkers for CRPC patients. Prospective validation is needed for further development of these candidate miRNAs. Patient summary In this study, we evaluated whether small RNAs circulating in blood could be used to predict clinical outcomes in late-stage prostate cancer patients. We identified two blood-based small RNAs whose levels showed significant association with survival. Our results warrant

  18. Quercetin-loaded nanomicelles to circumvent human castration-resistant prostate cancer in vitro and in vivo

    NASA Astrophysics Data System (ADS)

    Zhao, Jing; Liu, Juan; Wei, Tuo; Ma, Xiaowei; Cheng, Qiang; Huo, Shuaidong; Zhang, Chunqiu; Zhang, Yanan; Duan, Xianglin; Liang, Xing-Jie

    2016-02-01

    Prostate cancer is highly prevalent and has become the second leading cause of cancer-related death in men. Its treatment remains a challenge in the clinic, particularly in patients who have advanced to ``castration-resistant prostate cancer'' (CRPC). Thus, more effective therapeutic strategies are required. Quercetin (QCT) is a natural flavonoid compound that has attracted increasing interest due to its anticancer activity. However, the clinical application of quercetin is largely hampered by its poor water solubility and low bioavailability. The objective of this study was to evaluate the therapeutic potential of novel QCT-loaded nanomicelles (M-QCTs) assembled from DSPE-PEG2000 for prostate cancer treatment. Our results indicated that QCT was efficiently encapsulated into micelles up to 1 mg mL-1, which corresponds to a 450-fold increase of its water solubility. In vitro studies showed that the half-maximal inhibitory concentration (IC50) value (20.2 μM) of M-QCTs was much lower than free QCT (>200 μM). Thus, M-QCTs were considerably more effective than free QCT in proliferation inhibition and apoptosis induction of human androgen-independent PC-3 cells. Furthermore, M-QCTs showed superior antitumor efficacy and the tumor proliferation rate reduced by 52.03% compared to the control group in the PC-3 xenograft mouse model, possibly due to increased accumulation of M-QCTs at the tumor site by the enhanced permeability and retention (EPR) effect. Collectively, our studies demonstrated that M-QCTs significantly increase drug accumulation at the tumor site and exhibit superior anticancer activity in prostate cancer. Thus, our nanomicelle-based drug delivery system constitutes a promising and effective therapeutic strategy for clinical treatment.Prostate cancer is highly prevalent and has become the second leading cause of cancer-related death in men. Its treatment remains a challenge in the clinic, particularly in patients who have advanced to ``castration-resistant

  19. Quercetin-loaded nanomicelles to circumvent human castration-resistant prostate cancer in vitro and in vivo

    NASA Astrophysics Data System (ADS)

    Zhao, Jing; Liu, Juan; Wei, Tuo; Ma, Xiaowei; Cheng, Qiang; Huo, Shuaidong; Zhang, Chunqiu; Zhang, Yanan; Duan, Xianglin; Liang, Xing-Jie

    2016-02-01

    Prostate cancer is highly prevalent and has become the second leading cause of cancer-related death in men. Its treatment remains a challenge in the clinic, particularly in patients who have advanced to ``castration-resistant prostate cancer'' (CRPC). Thus, more effective therapeutic strategies are required. Quercetin (QCT) is a natural flavonoid compound that has attracted increasing interest due to its anticancer activity. However, the clinical application of quercetin is largely hampered by its poor water solubility and low bioavailability. The objective of this study was to evaluate the therapeutic potential of novel QCT-loaded nanomicelles (M-QCTs) assembled from DSPE-PEG2000 for prostate cancer treatment. Our results indicated that QCT was efficiently encapsulated into micelles up to 1 mg mL-1, which corresponds to a 450-fold increase of its water solubility. In vitro studies showed that the half-maximal inhibitory concentration (IC50) value (20.2 μM) of M-QCTs was much lower than free QCT (>200 μM). Thus, M-QCTs were considerably more effective than free QCT in proliferation inhibition and apoptosis induction of human androgen-independent PC-3 cells. Furthermore, M-QCTs showed superior antitumor efficacy and the tumor proliferation rate reduced by 52.03% compared to the control group in the PC-3 xenograft mouse model, possibly due to increased accumulation of M-QCTs at the tumor site by the enhanced permeability and retention (EPR) effect. Collectively, our studies demonstrated that M-QCTs significantly increase drug accumulation at the tumor site and exhibit superior anticancer activity in prostate cancer. Thus, our nanomicelle-based drug delivery system constitutes a promising and effective therapeutic strategy for clinical treatment.Prostate cancer is highly prevalent and has become the second leading cause of cancer-related death in men. Its treatment remains a challenge in the clinic, particularly in patients who have advanced to ``castration-resistant

  20. Persistent Neutrophil to Lymphocyte Ratio >3 during Treatment with Enzalutamide and Clinical Outcome in Patients with Castration-Resistant Prostate Cancer

    PubMed Central

    Conteduca, Vincenza; Crabb, Simon J.; Jones, Robert J.; Caffo, Orazio; Elliott, Tony; Scarpi, Emanuela; Fabbri, Paolo; Derosa, Lisa; Massari, Francesco; Numico, Gianmauro; Zarif, Sunnya; Hanna, Catherine; Maines, Francesca; Joyce, Helen; Lolli, Cristian; De Giorgi, Ugo

    2016-01-01

    The baseline value of neutrophil to lymphocyte ratio (NLR) has been found to be prognostic in patients with metastatic castration resistant prostate cancer (CRPC). We evaluated the impact of baseline NLR and its change in patients receiving enzalutamide. We included consecutive metastatic CRPC patients treated with enzalutamide after docetaxel and studies the change of NLR (>3 vs ≤3) after week 4 and 12 weeks. Progression-free survival (PFS), overall survival (OS) and their 95% Confidence Intervals (95% CI) were estimated by the Kaplan-Meier method and compared with the log-rank test. The impact of NLR on PFS and OS was evaluated by Cox regression analyses and on prostate-specific antigen response rates (PSA RR; PSA decline >50%) were evaluated by binary logistic regression. Data collected on 193 patients from 9 centers were evaluated. Median age was 73.1 years (range, 42.8–90.7). The median baseline NLR was 3.2. The median PFS was 3.2 months (95% CI = 2.7–4.2) in patients with baseline NLR >3 and 7.4 months (95% CI = 5.5–9.7) in those with NLR ≤3, p < 0.0001. The median OS was 10.4 months (95% CI = 6.5–14.9) in patients with baseline NLR >3 and 16.9 months (95% CI = 11.2–20.9) in those with baseline NLR ≤3, p < 0.0001. In multivariate analysis, changes in NLR at 4 weeks were significant predictors of both PFS [hazard ratio (HR) 1.24, 95% confidence interval (95% CI) 1.07–1.42, p = 0.003, and OS (HR 1.29, 95% CI 1.10–1.51, p = 0.001. A persistent NLR >3 during treatment with enzalutamide seems to have both prognostic and predictive value in CRPC patients. PMID:27434372

  1. Persistent Neutrophil to Lymphocyte Ratio >3 during Treatment with Enzalutamide and Clinical Outcome in Patients with Castration-Resistant Prostate Cancer.

    PubMed

    Conteduca, Vincenza; Crabb, Simon J; Jones, Robert J; Caffo, Orazio; Elliott, Tony; Scarpi, Emanuela; Fabbri, Paolo; Derosa, Lisa; Massari, Francesco; Numico, Gianmauro; Zarif, Sunnya; Hanna, Catherine; Maines, Francesca; Joyce, Helen; Lolli, Cristian; De Giorgi, Ugo

    2016-01-01

    The baseline value of neutrophil to lymphocyte ratio (NLR) has been found to be prognostic in patients with metastatic castration resistant prostate cancer (CRPC). We evaluated the impact of baseline NLR and its change in patients receiving enzalutamide. We included consecutive metastatic CRPC patients treated with enzalutamide after docetaxel and studies the change of NLR (>3 vs ≤3) after week 4 and 12 weeks. Progression-free survival (PFS), overall survival (OS) and their 95% Confidence Intervals (95% CI) were estimated by the Kaplan-Meier method and compared with the log-rank test. The impact of NLR on PFS and OS was evaluated by Cox regression analyses and on prostate-specific antigen response rates (PSA RR; PSA decline >50%) were evaluated by binary logistic regression. Data collected on 193 patients from 9 centers were evaluated. Median age was 73.1 years (range, 42.8-90.7). The median baseline NLR was 3.2. The median PFS was 3.2 months (95% CI = 2.7-4.2) in patients with baseline NLR >3 and 7.4 months (95% CI = 5.5-9.7) in those with NLR ≤3, p < 0.0001. The median OS was 10.4 months (95% CI = 6.5-14.9) in patients with baseline NLR >3 and 16.9 months (95% CI = 11.2-20.9) in those with baseline NLR ≤3, p < 0.0001. In multivariate analysis, changes in NLR at 4 weeks were significant predictors of both PFS [hazard ratio (HR) 1.24, 95% confidence interval (95% CI) 1.07-1.42, p = 0.003, and OS (HR 1.29, 95% CI 1.10-1.51, p = 0.001. A persistent NLR >3 during treatment with enzalutamide seems to have both prognostic and predictive value in CRPC patients. PMID:27434372

  2. Acute Aortic Dissection Following Treatment for Castration-ResistantProstate Cancer.

    PubMed

    Horrill, Tara

    2016-07-01

    A 65-year-old man presents to the emergency department with increasing back pain. His history includes hypertension, peripheral neuropathy, duodenal ulcer, superior mesenteric vein thrombus, stage IIB colon cancer treated with surgery and adjuvant chemotherapy, renal cell carcinoma treated with surgery, and prostate cancer treated with surgery and radiation. He is otherwise healthy. His family history is positive for colon cancer. Physical examination found significantly elevated blood pressure and a computed tomography scan of the thoracic and lumbar spine was performed, with findings of a type B aortic dissection extending from the aberrant right subclavian artery down to the abdominal aorta.
. PMID:27314183

  3. A Phase 2 Study of Abiraterone Acetate in Japanese Men with Metastatic Castration-resistant Prostate Cancer Who Had Received Docetaxel-based Chemotherapy

    PubMed Central

    Satoh, Takefumi; Uemura, Hiroji; Tanabe, Kazunari; Nishiyama, Tsutomu; Terai, Akito; Yokomizo, Akira; Nakatani, Tatsuya; Imanaka, Keiichiro; Ozono, Seiichiro; Akaza, Hideyuki

    2014-01-01

    Objective In this Phase 2 multicenter study the efficacy and safety of oral abiraterone acetate (1000 mg/once daily) plus prednisolone (5 mg/twice daily) was evaluated in metastatic castration-resistant prostate cancer patients from Japan who had previously received docetaxel-based chemotherapy. Methods Men (aged ≥20 years) with metastatic castration-resistant prostate cancer (prostate-specific antigen levels: ≥5 ng/ml), who had received 1 or 2 cytotoxic chemotherapies (with ≥1 regimen being docetaxel) for prostate cancer, were enrolled in this open-label, single-arm study. Primary efficacy endpoint was proportion of patients achieving a ≥50% prostate-specific antigen decline from baseline (prostate-specific antigen response rate) after 12-week treatment. Safety and pharmacokinetics were also assessed. Results Confirmed prostate-specific antigen response rate by Week 12 was 28.3% (90% confidence interval: 17.6%; 41.1%) or 13 out of 46 (full analysis set) treated patients. However, total prostate-specific antigen response rate including confirmed and unconfirmed responses was 34.8% (90% confidence interval: 23.2%; 47.9%). Secondary efficacy endpoints and outcomes were: improvement in Eastern Cooperative Oncology Group performance status score by ≥1 unit: 7/16 patients (43.8%); objective radiographic response: complete response, partial response and stable disease in 0, 1/22 (4.5%) and 9/22 (40.9%) patients, respectively; pain palliation response: 9/16 (56.3%) patients. The most common adverse events (>20% patients) were upper respiratory tract infection (13/47, 27.7% patients) and hepatic function abnormal (10/47, 21.3% patients, Grade 3: 8.5%). All mineralocorticoid-related toxicities were Grade 1/2. Conclusions Abiraterone acetate plus prednisolone showed favorable efficacy in metastatic castration-resistant prostate cancer Japanese patients who had received chemotherapy. Abiraterone acetate plus prednisolone had an acceptable safety profile. Clinical

  4. Germline BRCA mutation does not prevent response to taxane-based therapy for the treatment of castration-resistant prostate cancer

    PubMed Central

    Gallagher, David J.; Cronin, Angel M.; Milowsky, Matthew I.; Morris, Michael J.; Bhatia, Jasmine; Scardino, Peter T.; Eastham, James A.; Offit, Kenneth; Robson, Mark E.

    2014-01-01

    Objective To investigate the relationship between BRCA mutation status and response to taxane-based chemotherapy, since BRCA mutation carriers with prostate cancer appear to have worse survival than non-carriers and docetaxel improves survival in patients with castration-resistant prostate cancer. Patients and Methods We determined BRCA mutation prevalence in 158 Ashkenazi Jewish (AJ) men with castration-resistant prostate cancer. Clinical data were collected as part of an institutional prostate cancer research database and through additional medical record review. Clinical records and DNA samples were linked through a unique identifier, anonymizing the samples before genetic testing for the AJ BRCA1/2 founder mutations. Response to taxane-based therapy was defined by the prostate-specific antigen nadir within 12 weeks of therapy. Results In all, 88 men received taxane-based treatment, seven of whom were BRCA carriers (three BRCA1, four BRCA2; 8%). Initial response to taxane was available for all seven BRCA carriers and for 69 non-carriers. Overall, 71% (54/76) of patients responded to treatment, with no significant difference between carriers (57%) and non-carriers (72%) (absolute difference 15%; 95% confidence interval −23% to 53%; P = 0.4). Among patients with an initial response, the median change in prostate-specific antigen was similar for BRCA carriers (−63%, interquartile range −71% to −57%) and non-carriers (−60%, interquartile range −78% to −35%) (P = 0.6). At last follow-up, all seven BRCA carriers and 49 non-carriers had died from prostate cancer. One BRCA2 carrier treated with docetaxel plus platinum survived 37 months. Conclusion In this small, hypothesis-generating study approximately half of BRCA carriers had a prostate-specific antigen response to taxane-based chemotherapy, suggesting that it is an active therapy in these individuals. PMID:21756279

  5. Vaccination of castration-resistant prostate cancer patients with TroVax (MVA-5T4) in combination with docetaxel: a randomized phase II trial.

    PubMed

    Harrop, Richard; Chu, Franklin; Gabrail, Nashat; Srinivas, Sandy; Blount, Daniel; Ferrari, Anna

    2013-09-01

    The attenuated vaccinia virus, modified vaccinia Ankara, has been engineered to deliver the tumor antigen 5T4 (TroVax®). Here, we report results from a randomized open-label phase II trial in castration-resistant prostate cancer patients in which TroVax was administered in combination with docetaxel and compared against docetaxel alone. The aim was to recruit 80 patients (40 per arm), but the study was terminated early due to recruitment challenges. Therefore, this paper reports the comparative safety and immunological and clinical efficacy in 25 patients, 12 of whom were treated with TroVax plus docetaxel and 13 with docetaxel alone. 5T4-specific immune responses were monitored throughout the study. Clinical responses were assessed by measuring changes in tumor burden by CT and bone scan and by quantifying PSA concentrations. TroVax was well tolerated in all patients. Of 10 immunologically evaluable patients, 6 mounted 5T4-specific antibody responses. Patients treated with TroVax plus docetaxel showed a greater median progression-free survival of 9.67 months compared with 5.10 months for patients on the docetaxel alone arm (P = 0.097; HR = 0.31; 95% CI 0.08-1.24). Importantly, a pre-treatment biomarker previously demonstrated to predict 5T4 immune response and treatment benefit showed a strong association with 5T4 antibody response and a statistically significant association with progression-free survival in patients treated with TroVax plus docetaxel, but not docetaxel alone. PMID:23877659

  6. Impact of pre-treatment prostate tissue androgen content on the prediction of castration-resistant prostate cancer development in patients treated with primary androgen deprivation therapy.

    PubMed

    Shibata, Y; Suzuki, K; Arai, S; Miyoshi, Y; Umemoto, S; Masumori, N; Kamiya, N; Ichikawa, T; Kitagawa, Y; Mizokami, A; Sugimura, Y; Nonomura, N; Sakai, H; Honma, S; Kubota, Y

    2013-05-01

    Great advances in tissue androgen analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) have made it possible to evaluate the tissue androgen content from a single needle prostate biopsy specimen. In this study, we investigated if pre-treatment androgen content in prostate biopsy specimens could predict their response to primary androgen deprivation therapy (ADT) and future castration-resistant prostate cancer (CRPC). One-hundred and sixty-five prostate cancer patients who received primary ADT were enrolled. They had received multiple core prostate needle biopsy at diagnosis, and an additional one needle biopsy specimen was obtained for tissue androgen determination using LC-MS/MS. The patients' prostate specific antigen (PSA) values were periodically followed during the treatment and patients were determined to have CRPC when their PSA value increased continuously to 25% above the nadir and a 2.0 ng/mL increase. A significant correlation was found between PSA value decline velocity (PSA half-time) after ADT and pre-ADT tissue androgen content. Twenty-three patients were determined to have CRPC. These CRPC patients had a significantly high concentration of tissue T (p < 0.01) and low concentration of tissue 5α-dihydrotestosterone (DHT) (p < 0.01), resulting in a higher tissue T/DHT ratio (p < 0.001). A multivariate Cox proportional hazard model revealed the pre-ADT tissue T/DHT ratio and Gleason score as independent predictors for CRPC development. By using the two statistically significant variables, the relative risk of CRPC development could be calculated. The results of this study suggest that the evaluation of prostate androgen content in a single needle biopsy specimen may be useful to predict future CRPC development after primary ADT. Further studies are required for the clinical application of T/DHT ratio evaluation. PMID:23444052

  7. The PREVAIL trial of enzalutamide in men with chemotherapy-naïve, metastatic castration-resistant prostate cancer: Post hoc analysis of Korean patients

    PubMed Central

    Theeuwes, Ad; Kwon, Dong Deuk; Choi, Young Deuk; Chung, Byung Ha; Lee, Hyun Moo; Lee, Kang Hyun; Lee, Sang Eun

    2016-01-01

    Purpose This post hoc analysis evaluated treatment effects, safety, and pharmacokinetics of enzalutamide in Korean patients in the phase 3, double-blind, placebo-controlled PREVAIL trial. Materials and Methods Asymptomatic or mildly symptomatic chemotherapy-naive men with metastatic castration-resistant prostate cancer that progressed on androgen deprivation therapy received 160 mg/d oral enzalutamide or placebo (1:1) until death or discontinuation due to radiographic progression or skeletal-related event and initiation of subsequent therapy. Coprimary end points were centrally assessed radiographic progression-free survival (rPFS) and overall survival (OS). Secondary end points included investigator-assessed rPFS, time to initiation of chemotherapy, time to prostate-specific antigen (PSA) progression, PSA response (≥50% decline), and time to skeletal-related event. Results Of 1,717 total patients, 78 patients were enrolled in Korea (enzalutamide, n=40; placebo, n=38). Hazard ratios (95% confidence interval) for enzalutamide versus placebo were 0.23 (0.02–2.24) for centrally assessed rPFS, 0.77 (0.28–2.15) for OS, 0.21 (0.08–0.51) for time to chemotherapy, and 0.31 (0.17–0.56) for time to PSA progression. A PSA response was observed in 70.0% of enzalutamide-treated and 10.5% of placebo-treated Korean patients. Adverse events of grade ≥3 occurred in 33% of enzalutamide-treated and 11% of placebo-treated Korean patients, with median treatment durations of 13.0 and 5.1 months, respectively. At 13 weeks, the plasma concentration of enzalutamide plus N-desmethyl enzalutamide was similar in Korean and non-Korean patients (geometric mean ratio, 1.04; 90% confidence interval, 0.97–1.10). Conclusions In Korean patients, treatment effects and safety of enzalutamide were consistent with those observed in the overall PREVAIL study population (ClinicalTrials.gov Identifier: NCT01212991). PMID:27195316

  8. The Evolving Biology of Castration-Resistant Prostate Cancer: Review of Recommendations From the Prostate Cancer Clinical Trials Working Group 3.

    PubMed

    Geethakumari, Praveen Ramakrishnan; Cookson, Michael S; Kelly, William Kevin

    2016-02-01

    In 2008, the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) developed consensus guidelines for clinical trial design and conduct that redefined trial endpoints, with a dual-objective paradigm: to (1) controlling, relieving, or eliminating disease manifestations at the start of treatment; and (2) preventing or delaying further disease manifestations. Clinical and translational research in prostate cancer has expanded our current-day understanding of the mechanisms of its pathogenesis, as well as the different clinicopathologic and molecular subtypes of the disease, and has improved the therapeutic armamentarium for the management of metastatic castration-resistant prostate cancer (CRPC). These new advances led to the development of the updated PCWG3 guidelines in 2015. In this review, we analyze our evolving understanding of the biology of CRPC, acquired resistance mechanisms, and emerging therapeutic targets in light of the updated PCWG3 guidelines. We present a joint perspective from the medical oncology and urologic disciplines on the ongoing efforts to advance clinical trial performance in order to discover new therapies for this fatal disease. PMID:26888794

  9. The tumor suppressor TERE1 (UBIAD1) prenyltransferase regulates the elevated cholesterol phenotype in castration resistant prostate cancer by controlling a program of ligand dependent SXR target genes

    PubMed Central

    Fredericks, William J.; Sepulveda, Jorge; Lal, Priti; Tomaszewski, John E.; Lin, Ming-Fong; McGarvey, Terry; Rauscher, Frank J; Malkowicz, S. Bruce

    2013-01-01

    Castrate-Resistant Prostate Cancer (CRPC) is characterized by persistent androgen receptor-driven tumor growth in the apparent absence of systemic androgens. Current evidence suggests that CRPC cells can produce their own androgens from endogenous sterol precursors that act in an intracrine manner to stimulate tumor growth. The mechanisms by which CRPC cells become steroidogenic during tumor progression are not well defined. Herein we describe a novel link between the elevated cholesterol phenotype of CRPC and the TERE1 tumor suppressor protein, a prenyltransferase that synthesizes vitamin K-2, which is a potent endogenous ligand for the SXR nuclear hormone receptor. We show that 50% of primary and metastatic prostate cancer specimens exhibit a loss of TERE1 expression and we establish a correlation between TERE1 expression and cholesterol in the LnCaP-C81 steroidogenic cell model of the CRPC. LnCaP-C81 cells also lack TERE1 protein, and show elevated cholesterol synthetic rates, higher steady state levels of cholesterol, and increased expression of enzymes in the de novo cholesterol biosynthetic pathways than the non-steroidogenic prostate cancer cells. C81 cells also show decreased expression of the SXR nuclear hormone receptor and a panel of directly regulated SXR target genes that govern cholesterol efflux and steroid catabolism. Thus, a combination of increased synthesis, along with decreased efflux and catabolism likely underlies the CRPC phenotype: SXR might coordinately regulate this phenotype. Moreover, TERE1 controls synthesis of vitamin K-2, which is a potent endogenous ligand for SXR activation, strongly suggesting a link between TERE1 levels, K-2 synthesis and SXR target gene regulation. We demonstrate that following ectopic TERE1 expression or induction of endogenous TERE1, the elevated cholesterol levels in C81 cells are reduced. Moreover, reconstitution of TERE1 expression in C81 cells reactivates SXR and switches on a suite of SXR target genes that

  10. Circulating cell-free AR and CYP17A1 copy number variations may associate with outcome of metastatic castration-resistant prostate cancer patients treated with abiraterone

    PubMed Central

    Salvi, S; Casadio, V; Conteduca, V; Burgio, S L; Menna, C; Bianchi, E; Rossi, L; Carretta, E; Masini, C; Amadori, D; Calistri, D; Attard, G; De Giorgi, U

    2015-01-01

    Background: This study aimed to investigate copy number variations (CNVs) of CYP17A1 and androgen receptor (AR) genes in serum cell-free DNA collected before starting abiraterone in 53 consecutive patients with castration-resistant prostate cancer (CRPC). Methods: Serum DNA was isolated and CNVs were analysed for AR and CYP17A1 genes using Taqman copy number assays. The association between CNVs and progression-free/overall survival (PFS/OS) was evaluated by the Kaplan–Meier method and log-rank test. Results: Median PFS of patients with AR gene gain was 2.8 vs 9.5 months of non-gained cases (P<0.0001). Patients with CYP17A1 gene gain had a median PFS of 2.8 months vs 9.2 months in the non-gained patients (P=0.0014). A lower OS was reported in both cases (AR: P<0.0001; CYP17A1: P=0.0085). Multivariate analysis revealed that PSA decline ⩾50%, AR and CYP17A1 CNVs were associated with shorter PFS (P<0.0001, P=0.0004 and P=0.0450, respectively), while performance status, PSA decline ⩾50%, AR CNV and DNA concentration were associated with OS (P=0.0021, P=0.0014, P=0.0026 and P=0.0129, respectively). Conclusions: CNVs of AR and CYP17A1 genes would appear to be associated with outcome of CRPC patients treated with abiraterone. PMID:25897673

  11. Systemic Therapy in Men With Metastatic Castration-Resistant Prostate Cancer: American Society of Clinical Oncology and Cancer Care Ontario Clinical Practice Guideline

    PubMed Central

    Basch, Ethan; Loblaw, D. Andrew; Oliver, Thomas K.; Carducci, Michael; Chen, Ronald C.; Frame, James N.; Garrels, Kristina; Hotte, Sebastien; Kattan, Michael W.; Raghavan, Derek; Saad, Fred; Taplin, Mary-Ellen; Walker-Dilks, Cindy; Williams, James; Winquist, Eric; Bennett, Charles L.; Wootton, Ted; Rumble, R. Bryan; Dusetzina, Stacie B.; Virgo, Katherine S.

    2014-01-01

    Purpose To provide treatment recommendations for men with metastatic castration-resistant prostate cancer (CRPC). Methods The American Society of Clinical Oncology and Cancer Care Ontario convened an expert panel to develop evidence-based recommendations informed by a systematic review of the literature. Results When added to androgen deprivation, therapies demonstrating improved survival, improved quality of life (QOL), and favorable benefit-harm balance include abiraterone acetate/prednisone, enzalutamide, and radium-223 (223Ra; for men with predominantly bone metastases). Improved survival and QOL with moderate toxicity risk are associated with docetaxel/prednisone. For asymptomatic/minimally symptomatic men, improved survival with unclear QOL impact and low toxicity are associated with sipuleucel-T. For men who previously received docetaxel, improved survival, unclear QOL impact, and moderate to high toxicity risk are associated with cabazitaxel/prednisone. Modest QOL benefit (without survival benefit) and high toxicity risk are associated with mitoxantrone/prednisone after docetaxel. No benefit and excess toxicity are observed with bevacizumab, estramustine, and sunitinib. Recommendations Continue androgen deprivation (pharmaceutical or surgical) indefinitely. Abiraterone acetate/prednisone, enzalutamide, or 223Ra should be offered; docetaxel/prednisone should also be offered, accompanied by discussion of toxicity risk. Sipuleucel-T may be offered to asymptomatic/minimally symptomatic men. For men who have experienced progression with docetaxel, cabazitaxel may be offered, accompanied by discussion of toxicity risk. Mitoxantrone may be offered, accompanied by discussion of limited clinical benefit and toxicity risk. Ketoconazole or antiandrogens (eg, bicalutamide, flutamide, nilutamide) may be offered, accompanied by discussion of limited known clinical benefit. Bevacizumab, estramustine, and sunitinib should not be offered. There is insufficient evidence to

  12. Restoration of the cellular secretory milieu overrides androgen dependence of in vivo generated castration resistant prostate cancer cells overexpressing the androgen receptor.

    PubMed

    Patki, Mugdha; Huang, Yanfang; Ratnam, Manohar

    2016-07-22

    It is believed that growth of castration resistant prostate cancer (CRPC) cells is enabled by sensitization to minimal residual post-castrate androgen due to overexpression of the androgen receptor (AR). Evidence is derived from androgen-induced colony formation in the absence of cell-secreted factors or from studies involving forced AR overexpression in hormone-dependent cells. On the other hand, standard cell line models established from CRPC patient tumors (e.g., LNCaP and VCaP) are hormone-dependent and require selection pressure in castrated mice to re-emerge as CRPC cells and the resulting tumors then tend to be insensitive to the androgen antagonist enzalutamide. Therefore, we examined established CRPC model cells produced by castration of mice bearing hormone-dependent cell line xenografts including CRPC cells overexpressing full-length AR (C4-2) or co-expressing wtAR and splice-variant AR-V7 that is incapable of ligand binding (22Rv1). In standard colony formation assays, C4-2 cells were shown to be androgen-dependent and sensitive to enzalutamide whereas 22Rv1 cells were incapable of colony formation under identical conditions. However, both C4-2 and 22Rv1 cells formed colonies in conditioned media derived from the same cells or from HEK293 fibroblasts that were proven to lack androgenic activity. This effect was (i) not enhanced by androgen, (ii) insensitive to enzalutamide, (iii) dependent on AR (in C4-2) and on AR-V7 and wtAR (in 22Rv1) and (iv) sensitive to inhibitors of several signaling pathways, similar to androgen-stimulation. Therefore, during progression to CRPC in vivo, coordinate cellular changes accompanying overexpression of AR may enable cooperation between hormone-independent activity of AR and actions of cellular secretory factors to completely override androgen-dependence and sensitivity to drugs targeting hormonal factors. PMID:27179779

  13. Sequential use of the androgen synthesis inhibitors ketoconazole and abiraterone acetate in castration-resistant prostate cancer and the predictive value of circulating androgens

    PubMed Central

    Kim, Won; Zhang, Li; Wilton, John H.; Fetterly, Gerald; Mohler, James L.; Weinberg, Vivian; Morse, Allison; Szmulewitz, Russell; Friedlander, Terence W.; Fong, Lawrence; Lin, Amy M.; Harzstark, Andrea; Molina, Arturo; Small, Eric J.; Ryan, Charles J.

    2014-01-01

    Purpose Patients previously treated with ketoconazole were excluded from phase III trials of abiraterone acetate due to potential overlapping mechanism of action. The purpose of this study was to determine the clinical utility of abiraterone and its impact on circulating androgens following ketoconazole. Experimental Design Chemotherapy-naïve patients with progressive metastatic castration-resistant prostate cancer (mCRPC) and prior ketoconazole therapy ≥28 days received abiraterone 1000 mg daily and prednisone 5 mg twice daily. The primary endpoint was the proportion of patients with PSA response, defined as ≥30% PSA decline at 12 weeks. H0=0.30 versus H1=0.50 (α=0.05, power=0.83). Circulating androgens levels were measured using liquid chromatography tandem mass spectrometry. Results 39 patients were included in the final analysis. Twenty (51%, 95%CI: 36–66%) patients had ≥30% PSA decline; the null hypothesis was rejected. Sixteen (41%) had ≥50% PSA decline. Median PFS was 16 weeks; median rPFS was 36 weeks. Samples for measurement of baseline androgens were available in 37 patients. The PSA response proportion was 59% in 29 patients with DHEA ≥ limit of quantitation (LOQ), compared to 13% in 8 patients with DHEA

  14. The AhR Ligand, TCDD, Regulates Androgen Receptor Activity Differently in Androgen-Sensitive versus Castration-Resistant Human Prostate Cancer Cells.

    PubMed

    Ghotbaddini, Maryam; Powell, Joann B

    2015-07-01

    The reported biological effects of TCDD include induction of drug metabolizing enzymes, wasting syndrome and tumor promotion. TCDD elicits most of its effects through binding the aryl hydrocarbon receptor (AhR). TCDD induced degradation of AhR has been widely reported and requires ubiquitination of the protein. The rapid depletion of AhR following TCDD activation serves as a mechanism to modulate AhR mediated gene induction. In addition to inducing AhR degradation, TCDD has been reported to induce degradation of hormone receptors. The studies reported here, evaluate the effect of TCDD exposure on androgen receptor (AR) expression and activity in androgen-sensitive LNCaP and castration-resistant C4-2 prostate cancer cells. Our results show that TCDD exposure does not induce AhR or AR degradation in C4-2 cells. However, both AhR and AR are degraded in LNCaP cells following TCDD exposure. In addition, TCDD enhances AR phosphorylation and induces expression of AR responsive genes in LNCaP cells. Our data reveals that TCDD effect on AR expression and activity differs in androgen-sensitive and castration-resistant prostate cancer cell models. PMID:26154658

  15. The AhR Ligand, TCDD, Regulates Androgen Receptor Activity Differently in Androgen-Sensitive versus Castration-Resistant Human Prostate Cancer Cells

    PubMed Central

    Ghotbaddini, Maryam; Powell, Joann B.

    2015-01-01

    The reported biological effects of TCDD include induction of drug metabolizing enzymes, wasting syndrome and tumor promotion. TCDD elicits most of its effects through binding the aryl hydrocarbon receptor (AhR). TCDD induced degradation of AhR has been widely reported and requires ubiquitination of the protein. The rapid depletion of AhR following TCDD activation serves as a mechanism to modulate AhR mediated gene induction. In addition to inducing AhR degradation, TCDD has been reported to induce degradation of hormone receptors. The studies reported here, evaluate the effect of TCDD exposure on androgen receptor (AR) expression and activity in androgen-sensitive LNCaP and castration-resistant C4-2 prostate cancer cells. Our results show that TCDD exposure does not induce AhR or AR degradation in C4-2 cells. However, both AhR and AR are degraded in LNCaP cells following TCDD exposure. In addition, TCDD enhances AR phosphorylation and induces expression of AR responsive genes in LNCaP cells. Our data reveals that TCDD effect on AR expression and activity differs in androgen-sensitive and castration-resistant prostate cancer cell models. PMID:26154658

  16. (18)F-FDG-PET/CT and (18)F-NaF-PET/CT in men with castrate-resistant prostate cancer.

    PubMed

    Zukotynski, Katherine A; Kim, Chun K; Gerbaudo, Victor H; Hainer, Jon; Taplin, Mary-Ellen; Kantoff, Philip; den Abbeele, Annick D Van; Seltzer, Steven; Sweeney, Christopher J

    2015-01-01

    To evaluate (18)F-labeled-fluorodeoxyglucose ((18)F-FDG-) and (18)F-labeled-sodium fluoride ((18)F-NaF-) positron emission tomography/computed tomography (PET/CT) as biomarkers in metastatic castrate-resistant prostate cancer (mCRPC). Nine men (53-75 years) in a phase 1 trial of abiraterone and cabozantinib had (18)F-FDG-PET/CT, (18)F-NaF-PET/CT and standard imaging ((99m)Tc-labeled-methylene-diphosphonate ((99m)Tc-MDP) bone scan and abdominal/pelvic CT) at baseline and after 8 weeks of therapy. Baseline disease was classified as widespread (18)F-FDG-avid, oligometastatic (18)F-FDG-avid (1 site), or non-(18)F-FDG-avid. Metabolic response was classified using European Organisation for Research and Treatment of Cancer (EORTC) criteria. Treatment response using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, Prostate Cancer Working Group 2 (PCWG2) guidelines and days on trial (DOT) were recorded. All men were followed for 1 year or until progression. Four men had (18)F-FDG-avid disease: two with widespread (DOT 53 and 76) and two with oligometastatic disease (DOT 231 and still on trial after 742+ days). Five men had non-(18)F-FDG-avid disease; three remained stable or improved (2 still on trial while one discontinued for non-oncologic reasons; DOT 225-563+), and 2 progressed (DOT 285 and 532). Despite the small sample size, Kaplan-Meier analysis showed a significant difference in progression free survival (PFS) between men with widespread (18)F-FDG-avid, oligometastatic (18)F-FDG-avid and non-(18)F-FDG-avid disease (p < 0.01). All men had (18)F-NaF-avid disease. Neither (18)F-NaF-avid disease extent nor intensity was predictive of treatment response. (18)F-FDG-PET/CT may be superior to (18)F-NaF-PET/CT and standard imaging in men with mCRPC on abiraterone and cabozantinib. (18)F-FDG-PET/CT may have potential to stratify men into 3 groups (widespread vs. oligometastatic (18)F-FDG-avid vs. non-(18)F-FDG-avid mCRPC) to tailor therapy. Further evaluation is

  17. Suppression of Heat Shock Protein 27 Using OGX-427 Induces Endoplasmic Reticulum Stress and Potentiates Heat Shock Protein 90 Inhibitors to Delay Castrate-resistant Prostate Cancer

    PubMed Central

    Lamoureux, François; Thomas, Christian; Yin, Min-Jean; Fazli, Ladan; Zoubeidi, Amina; Gleave, Martin E.

    2014-01-01

    Background Although prostate cancer responds initially to androgen ablation therapies, progression to castration-resistant prostate cancer (CRPC) frequently occurs. Heat shock protein (Hsp) 90 inhibition is a rational therapeutic strategy for CRPC that targets key proteins such as androgen receptor (AR) and protein kinase B (Akt); however, most Hsp90 inhibitors trigger elevation of stress proteins like Hsp27 that confer tumor cell survival and treatment resistance. Objective We hypothesized that cotargeting the cytoprotective chaperone Hsp27 and Hsp90 would amplify endoplasmic reticulum (ER) stress and treatment-induced cell death in cancer. Design, setting, and participants Inducible and constitutive Hsp27 and other HSPs were measured by real-time reverse transcription-polymerase chain reaction and immunoblot assays. The combinations of OGX-427 with Hsp90 inhibitors were evaluated in vitro for LNCaP cell growth and apoptosis and in vivo in CRPC LNCaP xenograft models. Outcome measurements and statistical analysis Tumor volumes were compared using the Kruskal-Wallis test. Overall survival was analyzed using Kaplan-Meier curves, and statistical significance was assessed with the log-rank test. Results and limitations Hsp90 inhibitors induced expression of HSPs in tumor cells and tissues in a dose- and time-dependent manner; in particular, Hsp27 mRNA and protein levels increased threefold. In vitro, OGX-427 synergistically enhanced Hsp90 inhibitor-induced suppression of cell growth and induced apoptosis by 60% as measured by increased sub-G1 fraction and poly(ADP-ribose) polymerase cleavage. These biologic events were accompanied by decreased expression of HSPs, Akt, AR, and prostate-specific antigen, and induction of ER stress markers (cleaved activating transcription factor 6, glucose-regulated protein 78, and DNA-damage-inducible transcript 3). In vivo, OGX-427 potentiated the anticancer effects of Hsp90 inhibitor PF-04929113 (orally, 25 mg/kg) to inhibit tumor

  18. A randomized phase II study of cediranib alone versus cediranib in combination with dasatinib in docetaxel resistant, castration resistant prostate cancer patients

    PubMed Central

    Spreafico, Anna; Chi, Kim N.; Sridhar, Srikala S.; Smith, David C.; Carducci, Michael A.; Kavsak, Peter; Wong, Tracy S.; Wang, Lisa; Ivy, S. Percy; Mukherjee, Som Dave; Kollmannsberger, Christian K.; Sukhai, Mahadeo A.; Takebe, Naoko; Kamel-Reid, Suzanne; Siu, Lillian L.

    2014-01-01

    Summary Background Activation of the vascular endothelial growth factor receptor (VEGFR) and the oncogenic Src pathway has been implicated in the development of castration-resistant prostate cancer (CRPC) in preclinical models. Cediranib and dasatinib are multi-kinase inhibitors targeting VEGFR and Src respectively. Phase II studies of cediranib and dasatinib in CRPC have shown single agent activity. Methods Docetaxel-pretreated CRPC patients were randomized to arm A: cediranib alone (20 mg/day) versus arm B: cediranib (20 mg/day) plus dasatinib (100 mg/day) given orally on 4-week cycles. Primary endpoint was 12-week progression-free survival (PFS) as per the Prostate Cancer Clinical Trials Working Group (PCWG2). Patient reported outcomes were evaluated using Functional Assessment of Cancer Therapy- Prostate (FACT-P) and Present Pain Intensity (PPI) scales. Correlative studies of bone turnover markers (BTM), including bone alkaline phosphate (BAP) and serum beta-C telopeptide (B-CTx) were serially assayed. Results A total of 22 patients, 11 per arm, were enrolled. Baseline demographics were similar in both arms. Median number of cycles =4 in arm A (range 1–12) and 2 in arm B (range 1–9). Twelve-week PFS was 73 % in arm A versus 18 % in arm B (p=0.03). Median PFS in months (arm A versus B) was: 5.2 versus 2.6 (95 % CI: 1.9–6.5 versus 1.4-not reached). Most common grade 3 toxicities were hypertension, anemia and thrombocytopenia in arm A and hypertension, diarrhea and fatigue in arm B. One treatment-related death (retroperitoneal hemorrhage) was seen in arm A. FACT-P and PPI scores did not significantly change in either arm. No correlation between BTM and PFS was seen in either arm. Conclusions Although limited by small numbers, this randomized study showed that the combination of VEGFR and Src targeted therapy did not result in improved efficacy and may be associated with a worse outcome than VEGFR targeted therapy alone in patients with CRPC. PMID:24788563

  19. Complete Biochemical (Prostate-specific Antigen) Response to Sipuleucel-T With Enzalutamide in Castration-resistant Prostate Cancer: A Case Report With Implications for Future Research

    PubMed Central

    Graff, Julie N.; Drake, Charles G.; Beer, Tomasz M.

    2016-01-01

    OBJECTIVE To describe the case of a patient with castration-resistant, metastatic prostate cancer who achieved a complete and durable biochemical response after treatment with sipuleucel-T while continuing with enzalutamide and to explore the immunologic basis for such a response. MATERIALS AND METHODS We obtained serial prostate-specific antigen (PSA) measurements and bone scans to assess the patient’s response to enzalutamide followed by the addition of sipuleucel-T. Using preclinical and clinical data, we describe his response through known immunobiologic mechanisms. RESULTS This patient’s PSA level became undetectable during treatment with enzalutamide and began to increase again after 14 months. He opted for treatment with sipuleucel-T, while continuing with the enzalutamide. This resulted in another complete PSA response 6 months after exposure to sipuleucel-T. CONCLUSION Sipuleucel-T typically does not produce significant PSA reductions, and, to the best of our knowledge, only 1 previous report of a durable complete PSA response in a patient with metastatic disease has been published. The timing of this response supports an immune mechanism. The biologic rationale for the combination, coupled with the clinical result observed in our patient, provides a basis for studies of the combination of sipuleucel-T and enzalutamide. PMID:23374810

  20. Bone Marrow Recovery and Subsequent Chemotherapy Following Radiolabeled Anti-Prostate-Specific Membrane Antigen Monoclonal Antibody J591 in Men with Metastatic Castration-Resistant Prostate Cancer

    PubMed Central

    Tagawa, Scott T.; Akhtar, Naveed H.; Nikolopoulou, Anastasia; Kaur, Gurveen; Robinson, Brian; Kahn, Renee; Vallabhajosula, Shankar; Goldsmith, Stanley J.; Nanus, David M.; Bander, Neil H.

    2013-01-01

    Radioimmunotherapy (RIT) has demonstrated efficacy with acceptable toxicity leading to approval in non-Hodgkin’s lymphoma, but has been slower to develop for the treatment of advanced solid tumors. Prostate cancer (PC) represents a good candidate for RIT based upon high exposure to circulating antibodies at common disease sites with a specific, highly expressed cell-surface antigen of prostate-specific membrane antigen. Four phase I and II trials utilizing 177Lu- or 90Y-J591 have been reported. Long-term toxicity and chemotherapy administration was analyzed. As expected, the only serious toxicity observed was myelosuppression. Grade 4 thrombocytopenia occurred in 33.3% without significant hemorrhage and grade 4 neutropenia occurred in 17.3% with 0.07% febrile neutropenia. Nearly all subjects (97.3%) recovered to grade 0 or 1 platelets and all had complete neutrophil recovery. The majority (81.3%) received chemotherapy at any time, with 61.3% receiving chemotherapy following RIT. Ten subjects underwent bone marrow biopsies at some point in their disease course following RIT for low counts; all had diffuse PC infiltration without evidence of myelodysplasia or leukemia. As expected, myelosuppression occurs following therapeutic doses of RIT for men with metastatic castration-resistant PC. However, toxicity is predictable and self-limited, with the majority of patients who do not refuse able to receive cytotoxic chemotherapy following RIT. PMID:23986881

  1. Efficacy, quality of life, and safety of cabazitaxel in Canadian metastatic castration-resistant prostate cancer patients treated or not with prior abiraterone

    PubMed Central

    Saad, Fred; Winquist, Eric; Hubay, Stacey; Berry, Scott; Assi, Hazem; Levesque, Eric; Aucoin, Nathalie; Czaykowski, Piotr; Lattouf, Jean-Baptiste; Alloul, Karine; Stewart, John; Sridhar, Srikala S.

    2016-01-01

    Introduction: In the TROPIC study, cabazitaxel improved overall survival in abiraterone-naïve metastatic castration-resistant prostate cancer (mCRPC) patients post-docetaxel. To evaluate cabazitaxel in routine clinical practice, an international, single-arm trial was conducted. Efficacy, safety, and quality of life (QoL) data were collected from Canadian patients enrolled. Overall survival and progression-free survival were not collected as part of this study. Importantly, prior abiraterone use was obtained and its impact on clinical parameters was examined. Methods: Sixty-one patients from nine Canadian centres were enrolled, with prior abiraterone use known for 60 patients. Prostate-specific antigen (PSA) response rate, safety, and impact on QoL life were analyzed as a function of prior abiraterone use. Results: Overall, 92% of patients were ECOG 0/1, 88% had bone metastases, and 25% visceral metastases. Patients treated without prior abiraterone (NoPriorAbi) (n=35, 58%) and with prior abiraterone (PriorAbi) (n=25, 42%) had similar baseline characteristics, except for age and prior cumulative docetaxel dose. Median number of cabazitaxel cycles received was similar between groups (NoPriorAbi=6, PriorAbi=7), as was PSA response rate (NoPriorAbi=36.4%, PriorAbi=45.0%, p=0.54). Almost one-third (31%) of patients received prophylactic granulocyte colony-stimulating factors. Most frequent Grade 3/4 toxicities were neutropenia (14.8%); anemia, febrile neutropenia, fatigue (each at 9.8%); and diarrhea (8.2%). No treatment-related adverse event leading to death was observed. QoL and pain were improved with no difference seen between groups. Treatment discontinuation was mainly due to disease progression (45.9%) and adverse events (32.8%). Conclusions: In routine clinical practice, cabazitaxel’s risk-benefit ratio in mCRPC patients previously treated with docetaxel seems to be maintained independent of prior abiraterone use. PMID:27217856

  2. Prospective Evaluation of Low-Dose Ketoconazole Plus Hydrocortisone (HC) in Docetaxel Pre-treated Castration-Resistant Prostate Cancer (CRPC) Patients

    PubMed Central

    Lo, Ernest N.; Beckett, Laurel A.; Pan, Chong-Xian; Robles, Daniel; Suga, Jennifer M.; Sands, Jacob M.; Lara, Primo N.

    2015-01-01

    Background Ketoconazole is a well-known CYP-17-targeted systemic treatment for castration-resistant prostate cancer (CRPC). However, most of the published data has been in the pre-chemotherapy setting; its efficacy in the post-chemotherapy setting has not been as widely described. Chemotherapy-naïve patients treated with attenuated doses of ketoconazole (200-300 mg three times daily) had prostate specific antigen (PSA) response rate (greater than 50% decline) of 21% to 62%. We hypothesized that low-dose ketoconazole would likewise possess efficacy and tolerability in the CRPC post-chemotherapy state. Methods Men with CRPC and performance status (PS) 0-3, adequate organ function and who had received prior docetaxel were treated with low-dose ketoconazole (200 mg PO three times daily) and hydrocortisone (20 mg PO qAM and 10 mg PO qPM) until disease progression. Primary endpoint was PSA response rate (greater than 50% reduction from baseline) where a PSA response rate of 25% was to be considered promising for further study (versus a null rate of less than 5%); 25 patients were required. Secondary endpoints included PSA response greater than 30% from baseline, progression-free survival (PFS), duration of stable disease, and evaluation of adverse events (AEs). Results Thirty patients were accrued with median age of 72 years (range 55-86) and median pre-treatment PSA of 73 ng/ml (range 7-11,420). Twenty-nine patients were evaluable for response and toxicity. PSA response (>50% reduction) was seen in 48% of patients; PSA response (>30% reduction) was seen in 59%. Median PFS was 138 days; median duration of stable disease was 123 days. Twelve patients experienced grade 3 or 4 AEs. Of the 17 grade 3 AEs, only 3 were attributed to treatment. None of the 2 grade 4 AEs was considered related to treatment. Conclusions In docetaxel pre-treated CRPC patients, low-dose ketoconazole and hydrocortisone is a well-tolerated, relatively inexpensive and clinically active treatment

  3. Clinical activity of enzalutamide in docetaxel-naïve and docetaxel-pretreated patients with metastatic castration-resistant prostate cancer

    PubMed Central

    Nadal, Rosa; Zhang, Zhe; Rahman, Hibba; Schweizer, Michael T.; Denmeade, Samuel R.; Paller, Channing J.; Carducci, Michael A.; Eisenberger, Mario A.; Antonarakis, Emmanuel S.

    2014-01-01

    Background Two randomized clinical trials have demonstrated a survival advantage with enzalutamide over placebo in both docetaxel (D)-pretreated and D-naïve metastatic castration-resistant prostate cancer (mCRPC) patients. Cross-resistance between androgen receptor-directed therapies and taxanes has been suggested, possibly leading to lower efficacy of enzalutamide in the post-D setting. Material and Methods We aimed to examine the impact of prior D treatment on the clinical activity of enzalutamide in patients with mCRPC. We retrospectively reviewed an institutional database to identify men with mCRPC treated with standard-of-care enzalutamide. Patients were classified as D-naïve or D-pretreated. The efficacy end points were prostate-specific antigen (PSA) response rates (≥50% PSA decline), time to PSA progression (TTPP) and clinical/radiographic progression-free survival (PFS) in response to enzalutamide. Differences between groups (D-naïve and D-pretreated) were assessed by univariate and multivariable analyses using logistic and Cox regression models. Results One-hundred-seven (107) consecutive patients were included: 60 were D-pretreated and 47 were D-naïve. PSA responses were 43.2% in D-naïve patients and 25.4% in D-pretreated patients (P=0.089). Median TTPP was 7.2 months (95% CI=4.5–17.2) in the D-naïve group versus 2.6 mo (95% CI=1.9–3.5) in the D-pretreated group (P<0.0001). Median PFS was not reached for D-naïve men and was 3.3 mo (95% CI=2.5–4.8) for D-pretreated men (P<0.0001). After adjusting for potential confounders including prior abiraterone use, differences remained statistically significant for TTPP (HR=2.32; 95% CI=1.19–4.50; P=0.013) and marginally significant for PFS (HR=1.90; 95% CI=0.94–3.84; P=0.073) in multivariable analyses. Among patients who achieved a PSA response to enzalutamide (n=34), results suggested a trend towards shorter duration of response in D-pretreated patients. Conclusions The clinical activity of

  4. Randomized phase II trial of docetaxel with or without PSA-TRICOM vaccine in patients with castrate-resistant metastatic prostate cancer: A trial of the ECOG-ACRIN cancer research group (E1809)

    PubMed Central

    McNeel, Douglas G; Chen, Yu-Hui; Gulley, James L; Dwyer, Alexander J; Madan, Ravi A; Carducci, Michael A; DiPaola, Robert S

    2015-01-01

    Anti-tumor vaccines have demonstrated efficacy in patients with castration-resistant metastatic prostate cancer. One vaccine, Prostvac-VF®, using a heterologous prime-boost strategy with vaccinia and fowlpox viral vectors encoding PSA, is currently being evaluated in a registration phase III multinational clinical trial. The current trial was planned to assess the clinical efficacy of this vaccine in patients with castration-resistant metastatic prostate cancer receiving subsequent docetaxel chemotherapy. 10 patients with metastatic castration-resistant prostate cancer, with a predicted survival of at least 18 months, were enrolled out of a planned 144 patients. Eight of 10 patients were treated and were randomized to receive docetaxel chemotherapy alone (Arm B, n = 2) versus treatment with Prostvac-VF (days 1, 15, 29, 43, 57) followed by docetaxel (Arm A, n = 6) chemotherapy beginning at month 3. The primary endpoint of the trial was overall survival, and secondary endpoints included time to radiographic progression and immunological response. The trial was opened within the Eastern Cooperative Oncology Group, but due to slow accrual was closed by CTEP after only 10 patients were enrolled within 13 months. Results: Presented here are the safety, clinical, and immunological results from 8 eligible patients who underwent treatment. Two of 6 patients treated on Arm A, with vaccine followed by docetaxel, had a >50% PSA response, with one of these patients experiencing a PSA decline during treatment with vaccine. Significant PSA-specific CD4+ and CD8+ T-cell responses and IgG antibody responses specific for PSA were not detected. The primary endpoint of overall survival cannot be assessed due to limited accrual. The lack of T-cell responses, even in this small cohort, suggests that further validation and development of immune biomarkers will be important for future studies. Other trials remain ongoing to evaluate the role of anti-tumor vaccination in sequence

  5. Targeting Poly (ADP-Ribose) Polymerase and the c-Myb-TopBP1-ATR-Chk1 Signaling Pathway in Castration-Resistant Prostate Cancer

    PubMed Central

    Li, Likun; Chang, Wenjun; Yang, Guang; Ren, Chengzhen; Park, Sanghee; Karantanos, Theodoros; Karanika, Styliani; Wang, Jianxiang; Yin, Jianhua; Shah, Parantu K.; Takahiro, Hirayama; Dobashi, Masato; Zhang, Wenling; Efstathiou, Eleni; Maity, Sankar N.; Aparicio, Ana M.; Tapia, Elsa M Li Ning; Troncoso, Patricia; Broom, Bradley; Xiao, Lianchun; Lee, Hyun-Sung; Lee, Ju-Seog; Corn, Paul G.; Navone, Nora; Thompson, Timothy C.

    2014-01-01

    Androgen deprivation is the standard systemic treatment for advanced prostate cancer (PCa), but most patients ultimately develop castration-resistance. We show here that MYB is transcriptionally activated by androgen deprivation or impairment of androgen receptor (AR) signaling. MYB gene silencing significantly inhibited PCa growth in vitro and in vivo. Microarray data revealed that c-Myb shares a substantial subset of DNA damage response (DDR) target genes with AR, suggesting that c-Myb may replace AR for the dominant role in the regulation of their common DDR target genes in AR inhibition-resistant or AR-negative PCa. Gene signatures comprising AR, MYB, and their common DDR target genes are significantly correlated with metastasis, castration-resistance, recurrence, and shorter overall survival in PCa patients. We demonstrated in vitro that silencing of MYB, BRCA1 or TOPBP1 synergized with poly (ADP-ribose) polymerase (PARP) inhibitor olaparib (OLA) to increase cytotoxicity to PCa cells. We further demonstrated that targeting the c-Myb-TopBP1-ATR-Chk1 pathway by using the Chk1 inhibitor AZD7762 synergizes with OLA to increase PCa cytotoxicity. Our results reveal new mechanism-based therapeutic approaches for PCa by targeting PARP and the c-Myb-TopBP1-ATR-Chk1 pathway. PMID:24847116

  6. Clinical experience with radium-223 in the treatment of patients with advanced castrate-resistant prostate cancer and symptomatic bone metastases.

    PubMed

    Hague, Christina; Logue, John P

    2016-06-01

    The treatment of metastatic castrate-resistant prostate cancer (mCRPC) has grown over the past decade. The majority of patients develop bone metastases, which pose a significant burden on morbidity and mortality, especially skeletal-related events. Whilst demonstrating a favourable safety profile and improving symptoms, radiopharmaceuticals have until recently failed to show a survival benefit. However, since the large phase III randomized ALSYMPCA trial, the calcium mimetic properties of radium-223 (Ra223) have improved patients' quality of life and improved survival whilst keeping toxicities to a minimum. This review article summarizes the clinical data including our real life experience on the usage of the alpha emitter Ra223 in mCRPC, paying particular attention to how clinicians should best monitor response. PMID:27247627

  7. Clinical experience with radium-223 in the treatment of patients with advanced castrate-resistant prostate cancer and symptomatic bone metastases

    PubMed Central

    Hague, Christina; Logue, John P.

    2016-01-01

    The treatment of metastatic castrate-resistant prostate cancer (mCRPC) has grown over the past decade. The majority of patients develop bone metastases, which pose a significant burden on morbidity and mortality, especially skeletal-related events. Whilst demonstrating a favourable safety profile and improving symptoms, radiopharmaceuticals have until recently failed to show a survival benefit. However, since the large phase III randomized ALSYMPCA trial, the calcium mimetic properties of radium-223 (Ra223) have improved patients’ quality of life and improved survival whilst keeping toxicities to a minimum. This review article summarizes the clinical data including our real life experience on the usage of the alpha emitter Ra223 in mCRPC, paying particular attention to how clinicians should best monitor response. PMID:27247627

  8. The IncRNAs PCGEM1 and PRNCR1 are not implicated in castration resistant prostate cancer.

    PubMed

    Prensner, John R; Sahu, Anirban; Iyer, Matthew K; Malik, Rohit; Chandler, Benjamin; Asangani, Irfan A; Poliakov, Anton; Vergara, Ismael A; Alshalalfa, Mohammed; Jenkins, Robert B; Davicioni, Elai; Feng, Felix Y; Chinnaiyan, Arul M

    2014-03-30

    Long noncoding RNAs (IncRNAs) are increasingly implicated in cancer biology, contributing to essential cancer cell functions such as proliferation, invasion, and metastasis. In prostate cancer, several lncRNAs have been nominated as critical actors in disease pathogenesis. Among these, expression of PCGEM1 and PRNCR1 has been identified as a possible component in disease progression through the coordination of androgen receptor (AR) signaling (Yang et al., Nature 2013, see ref. [1]). However, concerns regarding the robustness of these findings have been suggested. Here, we sought to evaluate whether PCGEM1 and PRNCR1 are associated with prostate cancer. Through a comprehensive analysis of RNA-sequencing data (RNA-seq), we find evidence that PCGEM1 but not PRNCR1 is associated with prostate cancer. We employ a large cohort of >230 high-risk prostate cancer patients with long-term outcomes data to show that, in contrast to prior reports, neither gene is associated with poor patient outcomes. We further observe no evidence that PCGEM1 nor PRNCR1 interact with AR, and neither gene is a component of AR signaling. Thus, we conclusively demonstrate that PCGEM1 and PRNCR1 are not prognostic lncRNAs in prostate cancer and we refute suggestions that these lncRNAs interact in AR signaling. PMID:24727738

  9. MK591, a second generation leukotriene biosynthesis inhibitor, prevents invasion and induces apoptosis in the bone-invading C4-2B human prostate cancer cells: implications for the treatment of castration-resistant, bone-metastatic prostate cancer.

    PubMed

    Sarveswaran, Sivalokanathan; Ghosh, Ritisha; Morisetty, Shravan; Ghosh, Jagadananda

    2015-01-01

    Castration-resistant prostate cancer (CRPC) is a major clinical challenge for which no cure is currently available primarily because of the lack of proper understanding about appropriate molecular target(s). Previously we observed that inhibition of 5-lipoxygenase (5-Lox) activity induces apoptosis in some types of prostate cancer cells, suggesting an important role of 5-Lox in the viability of prostate cancer cells. However, nothing is known about the role of 5-Lox in the survival of castration-resistant, metastatic prostate cancer cells. Thus, we tested the effects of MK591, a second-generation, specific inhibitor of 5-Lox activity, on the viability and metastatic characteristics of CRPC cells. We observed that MK591 effectively kills the bone-invading C4-2B human prostate cancer cells (which bear characteristics of CRPC), but does not affect normal, non-cancer fibroblasts (which do not express 5-Lox) in the same experimental conditions. We also observed that MK591 dramatically inhibits the in vitro invasion and soft-agar colony formation of C4-2B cells. Interestingly, we found that treatment with MK591 dramatically down-regulates the expression of c-Myc and its targets at sub-lethal doses. In light of frequent over-activation of c-Myc in a spectrum of aggressive cancers (including CRPC), and the challenges associated with inhibition of c-Myc (because of its non-enzymatic nature), our novel findings of selective killing, and blockade of invasive and soft-agar colony-forming abilities of the castration-resistant, bone-metastatic C4-2B prostate cancer cells by MK591, open up a new avenue to attack CRPC cells for better management of advanced prostate cancer while sparing normal, non-cancer body cells. PMID:25875826

  10. Prostate-specific antigen response rate of sequential chemotherapy in castration-resistant prostate cancer: the results of real life practice

    PubMed Central

    Song, Geehyun; Lee, Chunwoo; You, Dalsan; Jeong, In Gab; Hong, Jun Hyuk; Ahn, Hanjong; Kim, Choung-Soo

    2013-01-01

    Purpose: Prostate-specific antigen (PSA) response rate (>50% PSA decline in pretreatment PSA following chemotherapy) carries a significant survival advantage in castration-resistant prostate cancer (CRPC). We compared PSA response rates in first-, second- and third-line chemotherapy after failure of previous chemotherapy according to chemotherapeutic agents. Methods: We retrospectively evaluated the oncological outcomes and PSA response rates of 384 patients with CRPC, who were treated with chemotherapy and had histologically proven adenocarcinoma of the prostate with failure after androgen ablation therapy between 1991 and 2012, at Asan Medical Center. Results: In 384 eligible patients, the median age was 67.5 years. The median pretreatment PSA and initial Gleason scores at baseline were 92.4 ng/mL (range, 2.0 to 6,370 ng/mL) and 9 (range, 6 to 10), respectively. The time from first diagnosis of prostate cancer to CRPC was 23 months (range, 1 to 164 months). As first-line chemotherapy, 245 patients (63.8%) received estramustine, 91 (23.7%) received docetaxel, and 39 (10.2%) received mitoxantrone. The PSA response rates were 39.6%, 51.6%, and 46.2%, respectively. Of 169 patients with second-line chemotherapy, estramustine was 15 (8.9%), docetaxel was 84 (49.7%), and mitoxantrone was 52 (30.8%). PSA response rates were 57.1%, 52%, and 28.0%, respectively. Of 81 patients with third-line chemotherapy, estramustine was 18 (22.2%), docetaxel was 16 (19.8%), and mitoxantrone was 28 (34.6%). The PSA response rates were 41.2%, 53.8%, and 11.1%, respectively. Declines in serum PSA levels of at least 50% occurred more frequently after treatment with docetaxel than with other chemo-agents regardless of second-and third-line chemotherapy. Even in third-line chemothrapy, docetaxel maintained the PSA response rate, whereas the PSA response rate of other agents, including mitoxantrone, decreased in patients in whom prior therapy failed. Conclusions: Docetacel was the most