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Journal ArticleDOI

Resistance to second-generation androgen receptor antagonists in prostate cancer.

19 Mar 2021-Nature Reviews Urology (Nature Publishing Group)-Vol. 18, Iss: 4, pp 209-226
TL;DR: The use of second-generation androgen receptor antagonists (SG-ARAs) has greatly impacted the treatment of metastatic prostate cancer, providing tolerable and efficacious alternatives to chemotherapy as mentioned in this paper.
Abstract: The introduction of second-generation androgen receptor antagonists (SG-ARAs) has greatly impacted the treatment of metastatic prostate cancer, providing tolerable and efficacious alternatives to chemotherapy. SG-ARAs provide similar therapeutic benefit to abiraterone, a potent CYP17 inhibitor, and do not require the co-administration of prednisone. Despite considerable improvements in clinical outcomes in the settings of both castration sensitivity and castration resistance, the durability of clinical response to the SG-ARAs enzalutamide, apalutamide and darolutamide, similar to abiraterone, is limited by inevitable acquired resistance. Genomic aberrations that confer resistance to SG-ARAs or provide potential alternative treatment modalities have been identified in numerous studies, including alterations of the androgen receptor, DNA repair, cell cycle, PI3K-AKT-mTOR and Wnt-β-catenin pathways. To combat resistance, researchers have explored approaches to optimizing the utility of available treatments, as well as the use of alternative agents with a variety of targets, including AR-V7, AKT, EZH2 and HIF1α. Ongoing research to establish predictive biomarkers for the treatment of tumours with resistance to SG-ARAs led to the approval of the PARP inhibitors olaparib and rucaparib in pre-treated metastatic castration-resistant prostate cancer. The results of ongoing studies will help to shape precision medicine in prostate cancer and further optimize treatment paradigms to maximize clinical outcomes.
Citations
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Journal ArticleDOI
TL;DR: In this article , the authors discuss how nongenetic factors contribute to heterogeneity of prostate cancer and summarize the challenges targeting the tumor environments, and emphasize that continued exploration of tumor heterogeneity is needed in order to offer a personalized therapy for advanced prostate cancer patients.
Abstract: Prostate cancer is characterized by a high degree of heterogeneity, which poses a major challenge to precision therapy and drug development. In this review, we discuss how nongenetic factors contribute to heterogeneity of prostate cancer. We also discuss tumor heterogeneity and phenotypic switching related to anticancer therapies. Lastly, we summarize the challenges targeting the tumor environments, and emphasize that continued exploration of tumor heterogeneity is needed in order to offer a personalized therapy for advanced prostate cancer patients.

22 citations

Journal ArticleDOI
TL;DR: In this paper , the authors summarize the current state of AR antagonist development and highlight the emerging challenges of their clinical application and the potential resistance mechanisms, which might be addressed by combination therapies or the development of novel AR-targeted therapies.
Abstract: Abstract Prostate cancer is a hormone-dependent malignancy, whose onset and progression are closely related to the activity of the androgen receptor (AR) signaling pathway. Due to this critical role of AR signaling in driving prostate cancer, therapy targeting the AR pathway has been the mainstay strategy for metastatic prostate cancer treatment. The utility of these agents has expanded with the emergence of second-generation AR antagonists, which began with the approval of enzalutamide in 2012 by the United States Food and Drug Administration (FDA). Together with apalutamide and darolutamide, which were approved in 2018 and 2019, respectively, these agents have improved the survival of patients with prostate cancer, with applications for both androgen-dependent and castration-resistant disease. While patients receiving these drugs receive a benefit in the form of prolonged survival, they are not cured and ultimately progress to lethal neuroendocrine prostate cancer (NEPC). Here we summarize the current state of AR antagonist development and highlight the emerging challenges of their clinical application and the potential resistance mechanisms, which might be addressed by combination therapies or the development of novel AR-targeted therapies.

17 citations

Journal ArticleDOI
TL;DR: The potential clinical utility of reversing intestinal dysbiosis and repairing acquired immune defects in PC patients is suggested, as compared with HSPC controls, CRPC patients demonstrated a shift in their intestinal microbiota that significantly correlated with sjTRECs.
Abstract: Background Prostate cancer (PC) responds to androgen deprivation therapy (ADT) usually in a transient fashion, progressing from hormone-sensitive PC (HSPC) to castration-resistant PC (CRPC). We investigated a mouse model of PC as well as specimens from PC patients to unravel an unsuspected contribution of thymus-derived T lymphocytes and the intestinal microbiota in the efficacy of ADT. Methods Preclinical experiments were performed in PC-bearing mice, immunocompetent or immunodeficient. In parallel, we prospectively included 65 HSPC and CRPC patients (Oncobiotic trial) to analyze their feces and blood specimens. Results In PC-bearing mice, ADT increased thymic cellularity and output. PC implanted in T lymphocyte-depleted or athymic mice responded less efficiently to ADT than in immunocompetent mice. Moreover, depletion of the intestinal microbiota by oral antibiotics reduced the efficacy of ADT. PC reduced the relative abundance of Akkermansia muciniphila in the gut, and this effect was reversed by ADT. Moreover, cohousing of PC-bearing mice with tumor-free mice or oral gavage with Akkermansia improved the efficacy of ADT. This appears to be applicable to PC patients because long-term ADT resulted in an increase of thymic output, as demonstrated by an increase in circulating recent thymic emigrant cells (sjTRECs). Moreover, as compared with HSPC controls, CRPC patients demonstrated a shift in their intestinal microbiota that significantly correlated with sjTRECs. While feces from healthy volunteers restored ADT efficacy, feces from PC patients failed to do so. Conclusions These findings suggest the potential clinical utility of reversing intestinal dysbiosis and repairing acquired immune defects in PC patients.

15 citations

Journal ArticleDOI
TL;DR: The identification of canonical genetic alterations and signaling pathway activation in prostate cancer has shed more insight into genetic background, molecular subtype and disease landscape of PC evolution, resulting in a more flexible role of individual therapies targeting diverse genotype and phenotype presentation as discussed by the authors.
Abstract: Prostate cancer (PC) is the most frequently diagnosed cancer and the second leading cause of cancer-related death in men in the Western society. Unfortunately, although the vast majority of patients are initially responsive to androgen-deprivation therapy (ADT), most cases eventually develop from hormone-sensitive prostate cancer (HSPC) to castration-resistant prostate cancer (CRPC). The main reason is PC heterogeneity and evolution during therapy. PC evolution is a continuously progressive process with combination of genomic alterations including canonical AR, TMPRSS2-ERG fusion, SPOP/FOXA1, TP53/RB1/PTEN, BRCA2. Meanwhile, signaling pathways including PI3K, WNT/β-catenin, SRC, IL-6/STAT3 are activated, to promote epithelial mesenchymal transition (EMT), cancer stem cell (CSC)-like features/stemness and neuroendocrine differentiation (NED) of PC. These improve our understanding of the genotype-phenotype relationships. The identification of canonical genetic alterations and signaling pathway activation in PC has shed more insight into genetic background, molecular subtype and disease landscape of PC evolution, resulting in a more flexible role of individual therapies targeting diverse genotype and phenotype presentation.

11 citations

Journal ArticleDOI
07 May 2021-Cells
TL;DR: In this paper, the role of the androgen/androgen receptor (AR) axis in prostate cancer (PCa) progression towards its most aggressive, castration-resistant (CRPC) stage is analyzed.
Abstract: Understanding the molecular mechanisms underlying prostate cancer (PCa) progression towards its most aggressive, castration-resistant (CRPC) stage is urgently needed to improve the therapeutic options for this almost incurable pathology. Interestingly, CRPC is known to be characterized by a peculiar hormonal landscape. It is now well established that the androgen/androgen receptor (AR) axis is still active in CRPC cells. The persistent activity of this axis in PCa progression has been shown to be related to different mechanisms, such as intratumoral androgen synthesis, AR amplification and mutations, AR mRNA alternative splicing, increased expression/activity of AR-related transcription factors and coregulators. The hypothalamic gonadotropin-releasing hormone (GnRH), by binding to its specific receptors (GnRH-Rs) at the pituitary level, plays a pivotal role in the regulation of the reproductive functions. GnRH and GnRH-R are also expressed in different types of tumors, including PCa. Specifically, it has been demonstrated that, in CRPC cells, the activation of GnRH-Rs is associated with a significant antiproliferative/proapoptotic, antimetastatic and antiangiogenic activity. This antitumor activity is mainly mediated by the GnRH-R-associated Gαi/cAMP signaling pathway. In this review, we dissect the molecular mechanisms underlying the role of the androgen/AR and GnRH/GnRH-R axes in CRPC progression and the possible therapeutic implications.

10 citations

References
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Journal ArticleDOI
TL;DR: Enzalutamide significantly prolonged the survival of men with metastatic castration-resistant prostate cancer after chemotherapy, and was shown with respect to all secondary end points.
Abstract: Background Enzalutamide (formerly called MDV3100) targets multiple steps in the androgen-receptor–signaling pathway, the major driver of prostate-cancer growth. We aimed to evaluate whether enzalutamide prolongs survival in men with castration-resistant prostate cancer after chemotherapy. Methods In our phase 3, double-blind, placebo-controlled trial, we stratified 1199 men with castration-resistant prostate cancer after chemotherapy according to the Eastern Cooperative Oncology Group performance-status score and pain intensity. We randomly assigned them, in a 2:1 ratio, to receive oral enzalutamide at a dose of 160 mg per day (800 patients) or placebo (399 patients). The primary end point was overall survival. Results The study was stopped after a planned interim analysis at the time of 520 deaths. The median overall survival was 18.4 months (95% confidence interval [CI], 17.3 to not yet reached) in the enzalutamide group versus 13.6 months (95% CI, 11.3 to 15.8) in the placebo group (hazard ratio for de...

3,866 citations

Journal ArticleDOI
TL;DR: Gutman et al. as mentioned in this paper showed that the acid phosphatase of serum is reduced in metastatic carcinoma of the prostate by decreasing the activity of androgens through castration or estrogenic injections and that this enzyme is increased by injecting androgens.
Abstract: Carcinoma of the prostate gland is peculiarly favorable for endocrine investigation since frequent serial observations of the activity of phosphatases in serum were found to provide objective indices of activity of the neo/~i~m when the enzymes were increased in amount above normal. In the present paper data are given for the values of serum phosphatases in carcinoma of the prostate and in normal men. We shall demonstrate that the acid phosphatase of serum is reduced in metastatic carcinoma of the prostate by decreasing the activity of androgens through castration or estrogenic injections and that this enzyme is increased by injecting androgens. We have been unable to find previous observations indicating any relationship of hormones to carcinoma of the prostate gland. An enzyme capable of hydrolyzing phosphoric esters was discovered by Grosser and Husler (4) in intestinal mucosa and kidney. Robison (16) found that this enzyme was particularly high in activity in growing bone and cartilage and that its activity was greatest at pH 9 to 9.5. This ~alkaline phosphatase," was found by Kay (9) to be increased in the serum in certain bone diseases including metastasis of neoplasms to bone and later work has shown that among these conditions is carcinoma of the prostate. Davies (3) and Bamann and Riedel (1) discovered that there occurs in the spleen and kidney of swine and cattle, in addition to the alkaline phosphatase, a phosphatase with an activity maximum at pH 4.8. An enzyme believed to be identical with this "acid phosphatase" was found by Kutscher and Wolbergs (11) to be present in very large amount in the human prostate gland. This finding of great activity of acid phosphatase in the prostate gland was confirmed and extended to include prostatic cancer by Gutman, Sproul, and Gutman (7). The serum of certain patients with disseminated prostatic carcinoma was found by Gutman and Gutman (6) and Barringer and Woodard (2) to exhibit increased acid phosphatase activity. Robinson, Gutman, and Gutman'~I5) summarized the acid phosphatase activity levels of 44 patients with carcinoma of the prostate. They concluded that a marked rise in acid phosphatase in serum is associated with the appearance or spread of roentgenologically demonstrable skeletal metastases and implies dissemination of the primary tumor and thus is of unfavorable prognostic significance. METttODS AND MATERIALS

3,534 citations

Journal ArticleDOI
Dan R. Robinson1, Eliezer M. Van Allen2, Eliezer M. Van Allen3, Yi-Mi Wu1, Nikolaus Schultz4, Robert J. Lonigro1, Juan Miguel Mosquera, Bruce Montgomery5, Mary-Ellen Taplin3, Colin C. Pritchard5, Gerhardt Attard6, Gerhardt Attard7, Himisha Beltran, Wassim Abida4, Robert K. Bradley5, Jake Vinson4, Xuhong Cao1, Pankaj Vats1, Lakshmi P. Kunju1, Maha Hussain1, Felix Y. Feng1, Scott A. Tomlins, Kathleen A. Cooney1, David Smith1, Christine Brennan1, Javed Siddiqui1, Rohit Mehra1, Yu Chen4, Yu Chen8, Dana E. Rathkopf4, Dana E. Rathkopf8, Michael J. Morris4, Michael J. Morris8, Stephen B. Solomon4, Jeremy C. Durack4, Victor E. Reuter4, Anuradha Gopalan4, Jianjiong Gao4, Massimo Loda, Rosina T. Lis3, Michaela Bowden9, Michaela Bowden3, Stephen P. Balk10, Glenn C. Gaviola9, Carrie Sougnez2, Manaswi Gupta2, Evan Y. Yu5, Elahe A. Mostaghel5, Heather H. Cheng5, Hyojeong Mulcahy5, Lawrence D. True11, Stephen R. Plymate5, Heidi Dvinge5, Roberta Ferraldeschi7, Roberta Ferraldeschi6, Penny Flohr7, Penny Flohr6, Susana Miranda6, Susana Miranda7, Zafeiris Zafeiriou7, Zafeiris Zafeiriou6, Nina Tunariu7, Nina Tunariu6, Joaquin Mateo7, Joaquin Mateo6, Raquel Perez-Lopez6, Raquel Perez-Lopez7, Francesca Demichelis12, Francesca Demichelis8, Brian D. Robinson, Marc H. Schiffman8, David M. Nanus, Scott T. Tagawa, Alexandros Sigaras8, Kenneth Eng8, Olivier Elemento8, Andrea Sboner8, Elisabeth I. Heath13, Howard I. Scher4, Howard I. Scher8, Kenneth J. Pienta14, Philip W. Kantoff3, Johann S. de Bono6, Johann S. de Bono7, Mark A. Rubin, Peter S. Nelson, Levi A. Garraway3, Levi A. Garraway2, Charles L. Sawyers4, Arul M. Chinnaiyan 
21 May 2015-Cell
TL;DR: This cohort study provides clinically actionable information that could impact treatment decisions for affected individuals and identified new genomic alterations in PIK3CA/B, R-spondin, BRAF/RAF1, APC, β-catenin, and ZBTB16/PLZF.

2,713 citations

Journal ArticleDOI
03 Feb 2012-Cell
TL;DR: Oxygen homeostasis represents an organizing principle for understanding metazoan evolution, development, physiology, and pathobiology and rapid progress is being made in elucidating homeostatic roles of HIFs in many physiological systems, determining pathological consequences of H IF dysregulation in chronic diseases, and investigating potential targeting of Hifs for therapeutic purposes.

2,450 citations

Journal ArticleDOI
TL;DR: Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer.
Abstract: BACKGROUND: Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New treatment options are needed for patients with metastatic prostate cancer who have not received chemotherapy, in whom the disease has progressed despite androgen-deprivation therapy. METHODS: In this double-blind, phase 3 study, we randomly assigned 1717 patients to receive either enzalutamide (at a dose of 160 mg) or placebo once daily. The coprimary end points were radiographic progression-free survival and overall survival. RESULTS: The study was stopped after a planned interim analysis, conducted when 540 deaths had been reported, showed a benefit of the active treatment. The rate of radiographic progression-free survival at 12 months was 65% among patients treated with enzalutamide, as compared with 14% among patients receiving placebo (81% risk reduction; hazard ratio in the enzalutamide group, 0.19; 95% confidence interval [CI], 0.15 to 0.23; P<0.001). A total of 626 patients (72%) in the enzalutamide group, as compared with 532 patients (63%) in the placebo group, were alive at the data-cutoff date (29% reduction in the risk of death; hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P<0.001). The benefit of enzalutamide was shown with respect to all secondary end points, including the time until the initiation of cytotoxic chemotherapy (hazard ratio, 0.35), the time until the first skeletal-related event (hazard ratio, 0.72), a complete or partial soft-tissue response (59% vs. 5%), the time until prostate-specific antigen (PSA) progression (hazard ratio, 0.17), and a rate of decline of at least 50% in PSA (78% vs. 3%) (P<0.001 for all comparisons). Fatigue and hypertension were the most common clinically relevant adverse events associated with enzalutamide treatment. CONCLUSIONS: Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer. (Funded by Medivation and Astellas Pharma; PREVAIL ClinicalTrials.gov number, NCT01212991.).

2,426 citations