Cooperative steroidogenic inhibition for treatment of advanced prostate cancer

描述（由申请人提供）：前列腺癌是美国男性最常见的癌症原因和第二大癌症死亡原因。局部疾病可能通过放射或手术治愈;然而，晚期疾病仍然无法治愈。性腺睾酮的耗竭是晚期疾病的首要标准治疗。不幸的是，转移性疾病几乎总是以去势抵抗性前列腺癌（CRPC）的形式复发，这通常是这种疾病的致命形式。尽管性腺睾酮耗竭，CRPC仍然由雄激素的肿瘤内合成驱动。阻断CYP 17 A1的醋酸阿比特龙所带来的生存获益是CRPC进展中雄激素合成必要性的最佳证据。醋酸阿比特龙于2011年4月被美国食品和药物管理局批准用于治疗CRPC，对醋酸阿比特龙的初始或获得性耐药性现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，驱动CRPC进展的最有效的雄激素，意外地绕过睾酮。这一发现改变了潜在药物靶点的格局，并表明3？羟类固醇脱氢酶/异构酶（3？HSD）是潜在的重要和可行的药理学靶点。该建议的总体假设是，有效的药理学抑制3？HSD将是CRPC和对醋酸阿比特龙耐药的肿瘤的有效治疗。在目标1中，3的作用和要求？HSD 1和3？将定义用于CRPC发生和进展的HSD 2表达。在目的2中，研究了醋酸阿比特龙对3-脱氢表雄酮转化为雄烯二酮的影响。HSD 1和3？将对HSD 2进行表征。目标3是合成一系列甾体唑类化合物，并筛选重组3-唑类化合物的候选抑制剂。HSD 1和3？将鉴定出也抑制CYP 17 A1的HSD 2。该提案的最终预期受益是开发新的和改进的方法来治疗CRPC男性。

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.