Prostate cancer kills 39,000 Americans every year. Initially, the majority of patients respond well to androgen ablation but eventually the cancer often recurs. Our goal is to provide more effective treatment for veterans and other patients with androgen dependent and castrate recurrent (CRPC) prostate cancer. We have synthesized and identified a number of novel compounds that are potent inhibitors of 171-hydroxylase/C17,20-lyase (CYP17). Our lead drug candidate VN/124-1, is a potent CYP17 inhibitor that also binds to the androgen receptor and causes degradation of the AR in vitro and in vivo (42, 44). In LAPC4 human prostate cancer xenografts, tumor growth was inhibited to a greater extent by VN/124-1, than by castration, the clinically used antiandrogen bicalutamide or abiraterone at equivalent doses. Based on the antitumor efficacy of VN/124-1, the compound has been licensed to Tokai Pharmaceuticals Inc. for clinical development. A micronized formulation has proved to be orally active with an extended pharmacokinetic profile, most likely due to enterohepatic recirculation. It has also been shown that rats exhibit no safety signal (blood cells, blood chemistries, liver function tests) after 28 days of daily oral dosing at levels up to and including 2000 mg/kg day. In vitro studies have determined that this compound exhibits no genotoxicity in bacterial or mammalian test systems, minimal effect on the hERG mediated potassium currents in Human Embryonic Kidney cells and minimal effects on a panel of cytochrome P450 enzymes commonly used to predict drug-drug interactions. An IND has been approved by the FDA and phase 1 trials began in November, 2010 using the micronized oral formulation. To date, the compound has been very well tolerated and without adverse effects in the patients. The proposed studies will complement the clinical trials by extending investigations on the mechanism of VN/124-1 on AR degradation and its specificity for 171-hydroxylase/C17,20-lyase in Aim 1. In the event that the in vivo activities of the micronized compound are not optimal, we will investigate whether novel pro-drugs may improve bioavailability and efficacy of VN/124-1 in Aim 2. We will determine the effects of VN/124-1 at optimal dosing on tissue and serum androgen levels and also on tumor growth in the androgen sensitive graft model in Specific Aim 3 and compare the effects of VN/124-1 with abiraterone and bicalutamide.
In Aim 4, we will investigate the effects of VN/124-1 or the most potent pro-drug in a castrate recurrent prostate cancer model. Also, the combination of VN/124-1 with inhibitors of signaling pathway proteins that cross talk with the AR will be investigated. This strategy will be studied in models of castration and antiandrogen resistant prostate cancer. Completion of these studies should provide relevant information on the mechanisms and effects of VN/124-1 in androgen dependent and also CRPC that will guide the use of this compound in clinical trials to improve treatment of patients with prostate cancer.
The overall goal of this project is development of compounds to provide effective antitumor activity against androgen dependent and castrate recurrent prostatic cancer. Our strategy is to synthesize and identify compounds which achieve androgen blockade by inhibiting 171- hydroxylase/C17,20-lyase (CYP17). Our lead compound VN/124-1, also binds to the androgen receptor and causes its degradation. This inhibitor has greater antitumor activity than castration and current antiandrogens in androgen dependent tumors of mouse xenograft models. Phase 1 Clinical trials of VN/124-1 began in November, 2009. The proposed studies will complement these trials by extending investigations on the mechanism of VN/124-1 in vivo and by determining its antitumor efficacy in castrate recurrent prostate cancer as well as in androgen dependent prostate cancer. 3