Abstract PL04-01: Overcoming cancer drug resistance (2012)

Abstract Resistance to anti-androgen therapy is associated with increased expression of androgen receptor (AR) mRNA, AR gene amplification or AR mutation. Increased AR levels are necessary and sufficient to promote hormone-refractory growth in models and, paradoxically, alter the cellular response to classic AR antagonists such that they function as weak agonists. Therefore, second generation antiandrogens must overcome these resistance mechanisms. We searched for novel AR antagonists that might retain function in the context of increased AR expression through a cell-based screen. Using the high affinity AR agonist RU59063 as a starting point, we synthesized and screened over 200 compounds to construct a structure/activity profile that defines features of the scaffold essential for receptor binding and for maximal antagonism. We focused our further efforts on a novel compound MDV3100, which retains potent antiandrogen activity in cells expressing increased levels of AR, blocks AR function in mice and impairs the growth of LNCaP and LAPC-4 xenografts engineered to express high levels of AR, whereas bicalutamide had minimal activity. MDV3100 inhibits AR with 10-fold greater affinity than bicalutamide and functions through a novel mechanism of action that impairs nuclear translocation and DNA binding. MDV3100 produced sustained PSA responses (greater than 50% reduction) in about ∼55 percent of men with castrate-resistant prostate cancer in a 140 patient phase I-II clinical trial. In a phase III registration study of 1119 men with castration resistance, chemotherapy refractory prostate cancer, MDV3100 prolonged survival compared to best supportive care (18.4 months versus 13.6 months; hazard ratio 0.631). The heterogeneity of clinical response to anti-androgen therapy suggests additional molecular determinants of drug resistance. By conducting an integrated genomic analysis of 214 prostate cancers, we have defined a common set of molecular lesions and pathways that may define distinct subsets of prostate cancer as well as responder/non-responder populations to antiandrogen therapy. In preclinical models we found that tumors with PTEN loss are relatively insensitive to androgen ablation therapy due to reciprocal negative feedback between the AR and PI3K signaling pathways. PTEN-mediated resistance can be overcome with combined AR + PI3K pathway inhibition. Studies of these and other molecular abnormalities reveal unique features of prostate cancer progression with implications for downstream drug development. References Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, Rosenfeld MG, Sawyers CL. Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004 Jan;10(1):33-9. Epub 2003 Dec 21. PMID: 14702632. Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, Wongvipat J, Smith-Jones PM, Yoo D, Kwon A, Wasielewska T, Welsbie D, Chen CD, Higano CS, Beer TM, Hung DT, Scher HI, Jung ME, Sawyers CL. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009 May 8;324(5928):787-90. Epub 2009 Apr 9. PMID: 19359544. Scher HI, Beer TM, Higano CS, Anand A, Taplin ME, Efstathiou E, Rathkopf D, Shelkey J, Yu EY, Alumkal J, Hung D, Hirmand M, Seely L, Morris MJ, Danila DC, Humm J, Larson S, Fleisher M, Sawyers CL; Prostate Cancer Foundation/Department of Defense Prostate Cancer Clinical Trials Consortium. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet. 2010 Apr 24;375(9724):1437-46. Epub 2010 Apr 14. PMID: 20398925. Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, Arora VK, Kaushik P, Cerami E, Reva B, Antipin Y, Mitsiades N, Landers T, Dolgalev I, Major JE, Wilson M, Socci ND, Lash AE, Heguy A, Eastham JA, Scher HI, Reuter VE, Scardino PT, Sander C, Sawyers CL, Gerald WL. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010 Jul 13;18(1):11-22. Epub 2010 Jun 24. PMID: 20579941. Carver BS, Chapinski C, Wongvipat J, Hieronymus H, Chen Y, Chandarlapaty S, Arora VK, Le C, Koutcher J, Scher H, Scardino PT, Rosen N, Sawyers CL. Reciprocal Feedback Regulation of PI3K and Androgen Receptor Signaling in PTEN-Deficient Prostate Cancer. Cancer Cell. 2011 May 17;19(5):575-86. PMID:21575859. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr PL04-01. doi:1538-7445.AM2012-PL04-01