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: 8043299
• 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/8043299
• 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; Cancer Model; 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; 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. 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

描述（由申请人提供）： 前列腺癌每年杀死39，000美国人。最初，大多数患者对雄激素消融反应良好，但最终癌症往往复发。我们的目标是为退伍军人和其他雄激素依赖性和去势复发性（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许多新的化合物，它们是171-羟化酶/C17，20-裂解酶（CYP 17）的有效抑制剂。我们的先导候选药物VN/124-1是一种有效的CYP 17抑制剂，也与雄激素受体结合，并在体外和体内引起AR降解（42，44）。在LAPC 4人前列腺癌异种移植物中，VN/124-1对肿瘤生长的抑制程度大于去势、临床上使用的抗雄激素比卡鲁胺或阿比特龙在同等剂量下的抑制程度。基于VN/124-1的抗肿瘤功效，该化合物已被许可给东海制药公司。用于临床开发。微粉化制剂已被证明具有口服活性，具有延长的药代动力学特征，最可能是由于肝肠再循环。研究还表明，大鼠每日经口给药28天后，在高达2000 mg/kg（含）的剂量水平下未显示出安全性信号（血细胞、血液化学、肝功能检查）。体外研究已确定该化合物在细菌或哺乳动物试验系统中无遗传毒性，对人胚肾细胞中hERG介导的钾电流的影响极小，对一组常用于预测药物相互作用的细胞色素P450酶的影响极小。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，该化合物的耐受性非常好，并且在患者中没有不良反应。拟定研究将通过扩展VN/124-1对AR降解的机制及其对Aim 1中171-羟化酶/C17，20-裂解酶的特异性的研究来补充临床试验。在微粉化化合物的体内活性不是最佳的情况下，我们将研究新的前药是否可以改善目的2中VN/124-1的生物利用度和功效。我们将确定VN/124-1在最佳剂量下对组织和血清雄激素水平以及对特定目标3中的雄激素敏感移植模型中的肿瘤生长的影响，并将VN/124-1与阿比特龙和比卡鲁胺的影响进行比较。在目的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，将研究VN/124-1与与AR交叉的信号传导途径蛋白的抑制剂的组合。该策略将在去势和抗雄激素抵抗性前列腺癌模型中进行研究。这些研究的完成应提供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。 公共卫生相关性： 该项目的总体目标是开发化合物，以提供对雄激素依赖性和去势复发性前列腺癌的有效抗肿瘤活性。我们的策略是合成和鉴定通过抑制171-羟化酶/C17，20-裂解酶（CYP 17）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。这种抑制剂在小鼠异种移植模型的雄激素依赖性肿瘤中具有比去势和当前抗雄激素更大的抗肿瘤活性。VN/124-1的1期临床试验于2009年11月开始。拟议的研究将通过扩展VN/124-1体内机制的研究和确定其在去势复发性前列腺癌以及雄激素依赖性前列腺癌中的抗肿瘤疗效来补充这些试验。3