Cooperative steroidogenic inhibition for treatment of advanced prostate cancer

描述（由申请人提供）：前列腺癌是美国最常见的癌症原因，也是男性癌症死亡的第二大原因。局部疾病有可能通过放疗或手术治愈；然而，晚期疾病仍然无法治愈。睾丸激素的消耗是晚期疾病的前期标准治疗。不幸的是，转移性疾病几乎总是复发为去势抵抗性前列腺癌（CRPC），这通常是这种疾病的致命形式。尽管性腺睾酮耗竭，CRPC仍由肿瘤内雄激素合成驱动。阻断CYP17A1的醋酸阿比特龙所带来的生存益处，是CRPC进展中雄激素合成必要性的最佳证据。2011年4月，美国食品和药物管理局（fda）批准用于治疗CRPC的醋酸阿比特龙（abiraterone acetate）的初始或获得性耐药，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）的合成出乎意料地绕过睾酮，而DHT是驱动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3ß-羟基类固醇脱氢酶/异构酶（3ßHSD）是一个潜在的重要和可行的药理学靶点。该提案的首要假设是，有效的药物抑制3ßHSD将是CRPC和对醋酸阿比特龙耐药的肿瘤的有效治疗方法。在Aim 1中，将明确3ßHSD1和3ßHSD2表达在CRPC发生进展中的作用和要求。在Aim 2中，将表征醋酸阿比特龙对3ßHSD1和3ßHSD2从脱氢表雄酮转化为雄烯二酮的影响。在Aim 3中，将合成一系列甾体唑类药物，并鉴定重组3ß hsd1和3ß hsd2的候选抑制剂，这些抑制剂也抑制CYP17A1。这项建议的最终预期益处是开发新的和改进的治疗男性CRPC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 3ß-hydroxysteroid dehydrogenase/isomerase (3ßHSD) is a potentially important and viable pharmacologic target. The overarching hypothesis of this proposal is that effective pharmacologic inhibition of 3ßHSD will be an effective treatment for CRPC and tumors that are resistant to abiraterone acetate. In Aim 1, the role and requirement of 3ßHSD1 and 3ßHSD2 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 3ßHSD1 and 3ßHSD2 will be characterized. In Aim 3, a series of steroidal azoles will be synthesized and candidate inhibitors of recombinant 3ßHSD1 and 3ßHSD2 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.