New treatment for androgen sensitive and resistant prostate cancer

雄激素敏感性和耐药性前列腺癌的新疗法

• 批准号: 8696805
• 负责人: ANGELA M. BRODIE
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8696805
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; Ablation; Adverse effects; Aldosterone; American; Anabolism; Androgen Antagonists; Androgen Receptor; Androgens; Bicalutamide; Binding; Biological Availability; Blood Cells; Blood Chemical Analysis; Boston; CYP17A1 gene; Castration; Clinical; Clinical Trials; Complement; Cytochrome P450; Development; Dose; Drug Formulations; Drug Interactions; Drug Kinetics; Embryo; Enzymes; Event; Exhibits; FDA approved; Genes; Goals; Human; Hydrocortisone; In Vitro; Investigation; LAPC4; Lead; Licensing; Liver Function Tests; Lyase; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Messenger RNA; Mixed Function Oxygenases; Modeling; Mus; Oral; Oral Administration; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase I Clinical Trials; Positioning Attribute; Potassium; Prodrugs; Proteins; Rattus; Recurrence; Resistance; SCID Mice; Safety; Serum; Signal Pathway; Signal Transduction; Specificity; System; Testing; Therapeutic; Tissues; Transplantation; Veterans; Xenograft Model; Xenograft procedure; abiraterone; base; drug candidate; effective therapy; genotoxicity; improved; in vivo; inhibitor/antagonist; kidney cell; killings; novel; overexpression; prostate cancer model; receptor; tumor; tumor growth

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.

描述（由申请人提供）： 前列腺癌每年夺去 39,000 名美国人的生命。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患有雄激素依赖型和去势复发性 (CRPC) 前列腺癌的患者提供更有效的治疗。我们合成并鉴定了许多新型化合物，它们是 171-羟化酶/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，它还能与雄激素受体结合并在体外和体内引起 AR 降解 (42, 44)。在 LAPC4 人前列腺癌异种移植物中，VN/124-1 比去势（临床使用的抗雄激素比卡鲁胺或同等剂量的阿比特龙）更大程度地抑制肿瘤生长。基于VN/124-1的抗肿瘤功效，该化合物已授权Tokai Pharmaceuticals Inc.进行临床开发。微粉化制剂已被证明具有口服活性，并具有延长的药代动力学特征，很可能是由于肠肝再循环。研究还表明，大鼠每天口服剂量高达 2000 mg/kg（含）28 天后，没有表现出任何安全信号（血细胞、血液化学、肝功能测试）。体外研究已确定，该化合物在细菌或哺乳动物测试系统中不表现出遗传毒性，对人胚胎肾细胞中 hERG 介导的钾电流影响极小，对一组常用于预测药物间相互作用的细胞色素 P450 酶影响极小。 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。迄今为止，该化合物对患者的耐受性非常好，并且没有出现不良反应。拟议的研究将通过扩展对目标 1 中 VN/124-1 AR 降解机制及其对 171-羟化酶/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，我们将研究新型前药是否可以提高目标 2 中 VN/124-1 的生物利用度和功效。我们将确定 在特定目标 3 中，最佳剂量的 VN/124-1 对组织和血清雄激素水平以及对雄激素敏感移植模型中肿瘤生长的影响，并比较 VN/124-1 与阿比特龙和比卡鲁胺的影响。在目标 4 中，我们将研究 VN/124-1 或最有效的前药在去势复发性前列腺癌模型中的作用。此外，还将研究 VN/124-1 与与 AR 相互作用的信号通路蛋白抑制剂的组合。该策略将在去势和抗雄激素耐药性前列腺癌模型中进行研究。这些研究的完成应提供有关 VN/124-1 在雄激素依赖性和 CRPC 中的机制和作用的相关信息，这将指导该化合物在临床试验中的使用，以改善前列腺癌患者的治疗。