New treatment for androgen sensitive and resistant prostate cancer

描述(由申请人提供)： 每年有3.9万美国人死于前列腺癌。最初，大多数患者对雄激素消融反应良好，但最终癌症经常复发。我们的目标是为退伍军人和其他雄激素依赖和去势复发(CRPC)前列腺癌患者提供更有效的治疗。我们已经合成并鉴定了一些新的化合物，它们是171-羟基酶/C17，20-裂解酶(CYP17)的有效抑制剂。我们的主要候选药物VN/124-1是一种有效的CYP17抑制剂，它还与雄激素受体结合，在体外和体内导致AR的降解(42，44)。在LAPC4人前列腺癌移植瘤中，VN/124-1对肿瘤生长的抑制程度大于去势，临床上使用的同等剂量的抗雄激素比卡鲁胺或阿比特龙。基于VN/124-1的抗肿瘤功效，该化合物已被授权给东海制药公司进行临床开发。一种微粉化的制剂已被证明具有口服活性，具有延长的药代动力学曲线，很可能是由于肝肠循环。研究还表明，在每天口服剂量达到或超过2000 mg/kg的28天后，大鼠没有表现出安全信号(血细胞、血液化学、肝功能测试)。体外研究已经确定，该化合物在细菌或哺乳动物测试系统中没有遗传毒性，对人胚胎肾脏细胞HERG介导的钾电流的影响很小，对一组通常用于预测药物-药物相互作用的细胞色素P450酶的影响也很小。IND已获得FDA批准，并于2010年11月开始使用微粉化口服制剂进行1期试验。到目前为止，该化合物在患者中的耐受性很好，没有不良反应。建议的研究将通过扩展对VN/124-1对AR降解的机制及其对目标1中171-羟基酶/C17，20-裂解酶的特异性的研究来补充临床试验。如果微粉化化合物的体内活性不是最佳的，我们将在目标2中调查新的前体药物是否可以改善VN/124-1的生物利用度和疗效。我们将在特定目标3的雄激素敏感移植物模型中确定VN/124-1对组织和血清雄激素水平以及对肿瘤生长的影响，并比较VN/124-1与阿比特龙和比卡鲁胺的效果。在目标4中，我们将研究VN/124-1或最有效的前体药物在去势复发前列腺癌模型中的作用。此外，VN/124-1与与AR串扰的信号通路蛋白的抑制剂的结合也将被研究。这一策略将在去势和抗雄激素耐药前列腺癌模型中进行研究。这些研究的完成将提供有关VN/124-1在雄激素依赖中的机制和作用的相关信息，并将指导这种化合物在临床试验中的使用，以改善前列腺癌患者的治疗。 公共卫生相关性： 该项目的总体目标是开发化合物，以提供有效的抗肿瘤活性，对抗雄激素依赖和去势复发的前列腺癌。我们的策略是合成和鉴定通过抑制171-羟基酶/C17，20-裂解酶(CYP17)来实现雄激素阻断的化合物。我们的先导化合物VN/124-1也与雄激素受体结合并导致其降解。在雄激素依赖的小鼠异种移植瘤模型中，该抑制剂比去势和当前的抗雄激素具有更强的抗肿瘤活性。VN/124-1的第一阶段临床试验于2009年11月开始。拟议的研究将补充这些试验，扩大对VN/124-1体内机制的研究，并确定其在去势复发性前列腺癌和雄激素依赖型前列腺癌中的抗肿瘤效果。3.

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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