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Androgen Receptor signaling axis in castration-resistant prostate cancer Lucarelli Giuseppe, MD, PhD Urology and Kidney Transplantation Unit Dept of Emergency and Organ Transplantation University of Bari This program is supported by an educational donation provided by Castration Resistant Prostate Cancer Prostate cancer disease continuum Death Docetaxel/chemotherapy Castration Tumour volume 2nd-line hormonal therapies Bicalutamide Flutamide Nilutamide Abiraterone Cabazitaxel Local therapy* Continued AR signalling Symptoms Asymptomatic Non-metastatic Metastatic Hormone-sensitive Castration-resistant Time Kohli & Tindall. Mayo Clin Proc 2010;85:77–86. AR, androgen receptor CASTRATE RESISTANT PROSTATE CANCER PATHOPHYSIOLOGY Testosterone serum levels (ng/dl) Disease progression tumor burden (PSA levels) 150 100 50 Castration threshold Serum testosterone 20 0 time Stimulation of Tumor Growth De Bono ESMO Educational Program, Genitourinary Cancers 2010 modified The road to resistance Pathway AR dependence Mechanism Hypersensitive AR dependent AR amplification AR splice variants Promiscuous AR dependent AR mutation Outlaw AR dependent Cross-talk with GF signaling pathways Bypass AR indipendent Parallel survival pathways Lurker cells AR indipendent Epithelial stem cells AR amplification AR gene amplifications are observed in 20-25% of CRPC but they are very rare in primary tumors Chen CD et al, Nature Medicine 10, 33 - 39 (2004) Higher AR levels convert antagonists to agonists Chen CD et al, Nature Medicine 10, 33 - 39 (2004) AR splice variants Expression of Cell-cycle genes (UBE2C) Upregulation of steroidogenic enzymes AR mutations T877A mutant (Thr→Ala) E2/Prog L701H mutant (Leu→His) Double T877A L701H mutant (Zhao XY, Nat Med: 6, 2000) E2/Prog H874Y mutant (His→Tyr) Inappropriate interaction with AR coactivators DHT 100 nM DHT 100 nM Q640Stop mutation generates a constitutively activated mutant AR AR Coactivators Coactivators PCa Expression ARA70 Controversial data ARA54 Up-regulated ARA55 p300 SRC1 Up-regulated TIF2 PIAS RAC3 Up-regulated Up-regulated Up-regulated Function Enhances AR activities or Tumor suppressor? Enhances AR activation (Estradiol+Flutamide) ″ Ligand indipendent activation by IL-6 Enhances AR activation (Adrenal androgens) ″ Correlation with grade & stage AR coactivators augment functional activity of the receptor by interacting with histones and are implicated in ligand indipendent activation of the AR Outlaw receptor RAS ADT results in de-repression of alternative survival pathways and in recalibration of prostate cancer tissue androgen levels leading to partial restoration of AR transcriptional activity. Karantos et al. Oncogene 2013 (in press) MDV-3100-Enzalutamide Enzalutamide is an AR signalling inhibitor that inhibits AR signalling in three distinct ways: 2. Impairs nuclear translocation 1. Blocks AR binding Cytoplasm DHT Enzalutamide AR 3. Blocks DNA binding and activation Nucleus Enzalutamide 2–3 fold lower affinity than DHT Tran et al. Science 2009;324:787–90; Watson et al. Proc Natl Acad Sci USA 2010;107:16759–65. Enzalutamide Androgen metabolism in prostate cancer Intratumoral androgens in CRPC tumors are maintained at levels sufficient to activate the AR signaling pathway Activated steroidogenesis pathways provide an adaptive response to ADT, facilitating CRPC tumor survival in a low exogenous androgen environment. The maintenance of intratumoral androgens can be accounted for in part by intratumoral or intracrine biosynthesis of steroid hormones, either via the uptake and conversion of adrenal androgens or potentially via de novo steroidogenesis. Classic pathway Backdoor pathway Expression of steroidogenic enzyme transcripts in primary and metastatic prostate tumors Soft tissue metastases from CRPC shows elevated testosterone compared to primary tumors Transcripts encoding all enzymes involved in the sequential biosynthesis of testosterone and DHT from cholesterol precursors were expressed in the majority of castration-resistant metastatic tumors examined Montgomery RB, Cancer Res 2008;11, 68 Meccanismo d’azione di abiraterone Steroidogenesi ipokaliemia Ipertensione sovraccarico di fluidi Cholesterol Desmolase Renin-angiotensin Pregnenolone Pregnenolo Progesterone Deoxycorticosterone Corticosterone Aldosterone CYP17 X 17αhydroxylase 17α –OHprogesterone 17α-OHpregnenolone 11-Deoxycortisol Cortisol ACTH X CYP17 C17,20-lyase 5α-reductase DHEA Androstenedione Testosterone DHT CYP19: aromatasi Abiraterone Estradiolo Yang, Drugs. 2011; Attard, JCO 2008 Meccanismo d’azione di abiraterone Steroidogenesi Cholesterol Basse dosi di steroidi minimizzano la tossicità mineralcoticoide - correlata Desmolase Renin-angiotensin Pregnenolone Progesterone Deoxycorticosterone Corticosterone Aldosterone CYP17 X 17αhydroxylase 17α –OHprogesterone 17α-OHpregnenolone 11-Deoxycortisol Cortisol ACTH X CYP17 C17,20-lyase 5α-reductase DHEA Androstenedione Testosterone DHT CYP19: aromatasi Abiraterone + prednisone Estradiolo Yang, Drugs. 2011; Attard, JCO 2008 Stromal-epithelial interactions and intratumoral androgen biosynthesis Alterations in androgen transport normal BPH SLCO1B3 PCa Wright JL, Cancer Epidemiol Biomarkers Prev. 2011 Conclusions Persistent activation of AR signaling in CRPC suggests that a majority of prostate cancers progress through pathways that continue to activate the cellular AR program. While the introduction of potent steroidogenic inhibitors such as abiraterone, in combination with novel AR inhibitors such as MDV3100, holds significant promise for the concept of multitargeted AR pathway blockade, the optimal timing, sequence, and potential combinatorial strategies using new AR pathway inhibitors are critical unanswered questions in the treatment of men with CRPC. Prostate cancer is not the only cause of death in men
