Abstract CN08-01: Targeting the androgen receptor in castration-resistant prostate cancer.

Mortality from prostate cancer in 2011 is estimated at 33,720 deaths in United States which occurs primarily in advanced disease stages. The cornerstone treatment of advanced prostate cancer is androgen deprivation, first established by Huggins and Hodges in 1941. Since then, recognition for the central role of the androgen axis and the androgen receptor (AR) during prostate tumorigenesis and progression, has been accepted. The arrest of the androgen-dependent growth stimulus by surgical or medical castration (with LHRH analogues or antagonists) is the result of reduced circulating androgens including dihydro-testosterone (DHT), which induces apoptotic regression of androgen-dependent cancer cells. This control however is short lived with the emergence of castration-resistant prostate cancer (CRPC). Despite achieving sub-castrate levels of circulating androgens as a result of castration, the androgen-AR axis continues to play an active role in tumor progression. A functional AR, despite the paucity of circulating androgens, is evidenced by the elevation of AR mRNA and re-expression of some androgen-regulated genes during clinical castration, indicative of a persistently activated AR cell signaling pathway. Furthermore, although testosterone and DHT are depleted in serum following traditional androgen deprivation therapy, significant levels of androgens have been measured in locally CRPC tissue1 as well as in metastatic CRPC tissue2. These androgens continue to regulate AR transcriptional activity and stimulate expression of androgen-regulated genes thereby re-invigorating tumor progression. Indeed, a number of molecular and cellular changes have been shown to facilitate activation of the AR under these conditions: amplification of the AR gene allow the receptor to respond to lower levels of androgens; splice variants of the AR exhibit constitutive activity; increased expression of several co-activator proteins enhance activation of the AR; other signaling pathways, including Akt-PI3 Kinase and MAP Kinase, activate the AR; and gain-of-function mutations in the AR allow the receptor to become “promiscuous” and then bind to ligands other than DHT, including anti-androgens3 and weaker sex steroids such as androstenedione. Abiraterone acetate, a selective steroidal irreversible inhibitor of CYP17 (17 hydroxylase/C17,20-lyase) blocks two important enzymatic activities in the synthesis of testosterone4. In a phase III trial in patients progressing on docetaxel chemotherapy, the combination of abiraterone plus prednisone resulted in an improvement in overall survival compared to patients receiving prednisone plus placebo (14.8 months vs 10.9 months, HR=0.646;P These results re-enforce the rationale behind previous similar clinical attempts in which non-selective and reversible inhibitors of sex steroid biosynthesis such as ketoconazole in combination with hydrocortisone were used6 to target androgen biosynthesis after failure of androgen deprivation therapy. Ketoconazole inhibits the cholesterol side chain cleavage enzyme 11 beta hydroxylase as well as CYP 17, albeit reversibly7. While no overall survival difference for the study group was demonstrated in this study, an increased survival was observed in patients treated with ketoconazole experiencing PSA responses (35% with a 50% decline in PSA). Interestingly, CYP 17 inhibition with abiraterone in CRPC patients may retain activity even in patients previously treated with ketoconazole8. Adverse events with abiraterone use include hypokalemia, hypertension, peripheral edema and headaches all sequelae of secondary mineralocorticoid excess which can be minimized with the use of combination prednisone. Additional drugs in development include Ortrenol (previously named TAK-700; Millenium Pharmaceuticals, Cambridge, MA/Takeda, Osaka, Japan), which inhibits CYP 17, 20 lyase more potently than 17-hydroxylase. Two on-going large phase III studies with ortrenol in combination with prednisone in chemotherapy naive (ClinicalTrials.gov Identifier: NCT 01193244) and in the post docetaxel chemotherapy (ClinicalTrials.gov Identifier: NCT01193257) CRPC populations will evaluate response of the study combination vs prednisone plus placebo with overall survival as the primary endpoint. Another novel drug is ToK-001 (Tokai Pharmaceuticals, Cambridge, MA) which is a combined inhibitor of CYP 17 and AR currently in early clinical phase II trials. Resistance to abiraterone has been observed in patients initially responding to the drug. Xenograft models suggest that the resistance may occur through upregulation of CYP17A1 and/or induction of AR and AR splice variants that confer ligand independent AR transactivation9. Targeting the AR with next generation AR inhibitors has also emerged as a potential therapeutic maneuver in CRPC. MDV310010 (Medivation, San Francisco, CA), a second generation anti-androgen, is now in phase III clinical trials. This new diarylthiohydantoin compound targets AR by binding over-expressed AR with an affinity that is several fold greater than previously obtained with anti-androgens (bicalutamide and flutamide). Another drug, ARN-509 (Aragon, San Diego, CA) is currently in phase I/II clinical trials (NCT01171898) and further development of this drug is to be determined based on the completion of the on-going dose establishing trial. Both these drugs disrupt the nuclear translocation of AR and impair DNA binding to androgen response elements and recruitment of co-activators and thus have multi-functional anti-tumor capabilities10. Results of a phase III study with the primary endpoint of overall survival evaluating MDV3100 vs placebo in the post chemotherapy, castration resistant stage which has completed accrual is now awaited (NCT00974311). Another phase III study is currently accruing patients after androgen deprivation failure who are chemotherapy naive evaluating MDV3100 vs placebo also with the primary endpoint of overall survival (NCT01212991). In conclusion, the AR signaling axis remains active during the progression to CRPC and should be considered to be a viable target for therapy. 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