Cooperative steroidogenic inhibition for treatment of advanced prostate cancer

描述(申请人提供)：前列腺癌是美国男性最常见的癌症原因，也是男性癌症死亡的第二大原因。局部疾病有可能通过放射或手术治愈；然而，晚期疾病仍然无法治愈。性腺睾丸素耗竭是晚期疾病的首要标准治疗方法。不幸的是，转移性疾病几乎总是复发为耐去势前列腺癌(CRPC)，这通常是这种疾病的致命形式。尽管性腺睾酮耗尽，CRPC仍然由瘤内雄激素的合成驱动。阻断细胞色素P17A1的醋酸阿比特龙所带来的生存益处是在慢性前列腺癌进展过程中雄激素合成的必要性的最好证据。2011年4月，美国食品和药物管理局(FDA)批准将醋酸阿比特龙用于治疗慢性前列腺癌，这种药物最初或获得性耐药，现在已成为下一个需要克服的障碍。最近的研究表明，双氢睾酮(DHT)的合成出人意料地绕过了睾酮。双氢睾酮是推动CRPC进展的最有效的雄激素。这一发现改变了潜在药物靶点的格局，并表明3？羟基类固醇脱氢酶/异构酶(3？HSD)是一个潜在的重要和可行的药理靶点。这一建议的主要假设是，有效的药物抑制3？HSD将是治疗CRPC和对醋酸阿比特龙耐药的肿瘤的有效方法。在目标1中，将明确3？HSD1和3？HSD2的表达在CRPC发生发展中的作用和要求。目的2研究醋酸阿比特龙对脱氢表雄酮转化为雄烯二酮的作用(S)。在目标3中，将合成一系列的甾体唑类化合物，并将确定重组的3？HSD1和3？HSD2的候选抑制剂，它们也对细胞色素P17A1有抑制作用。这项提议的最终预期好处是开发新的和改进的治疗慢性前列腺癌男性的方法。

DESCRIPTION (provided by applicant): Prostate cancer is the most common cause of cancer and second leading cause of cancer death for men in the United States. Localized disease is potentially curable with radiation or surgery; however, advanced disease remains incurable. Depletion of gonadal testosterone is the upfront standard therapy for advanced disease. Unfortunately, metastatic disease almost always recurs as castration-resistant prostate cancer (CRPC), which is generally the lethal form of this disease. Despite depletion of gonadal testosterone, CRPC remains driven by intratumoral synthesis of androgens. The survival benefit conferred by abiraterone acetate, which blocks CYP17A1, is the best evidence for the necessity of androgen synthesis in the progression of CRPC. Initial or acquired resistance to abiraterone acetate, which was approved by the United States Food and Drug Administration in April 2011 for the treatment of CRPC, has now become the next hurdle to overcome. Recent studies have shown that synthesis of dihydrotestosterone (DHT), the most potent androgen that drives CRPC progression, unexpectedly bypasses testosterone. This finding alters the landscape of potential drug targets and suggests that 3?-hydroxysteroid dehydrogenase/isomerase (3?HSD) is a potentially important and viable pharmacologic target. The overarching hypothesis of this proposal is that effective pharmacologic inhibition of 3?HSD will be an effective treatment for CRPC and tumors that are resistant to abiraterone acetate. In Aim 1, the role and requirement of 3?HSD1 and 3?HSD2 expression for the development and progression of CRPC will be defined. In Aim 2, the effect(s) of abiraterone acetate on the conversion from dehydroepiandrosterone to androstenedione by 3?HSD1 and 3?HSD2 will be characterized. In Aim 3, a series of steroidal azoles will be synthesized and candidate inhibitors of recombinant 3?HSD1 and 3?HSD2 will be identified, which also inhibit CYP17A1. The ultimate anticipated benefit of this proposal is the development of new and improved approaches to the treatment of men with CRPC.