Cooperative steroidogenic inhibition for treatment of advanced prostate cancer

协同类固醇生成抑制治疗晚期前列腺癌

• 批准号: 8644258
• 负责人: Nima Sharifi
• 金额: $ 31.71万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8644258
• 关键词: 3-Hydroxysteroid Dehydrogenases; Acetates; Androgens; Androstenedione; Azoles; Bypass; CYP17A1 gene; Cancer Etiology; Cessation of life; Development; Disease; Dose; Drug Targeting; Enzymes; Hydroxyl Radical; Hydroxysteroid Dehydrogenases; Isoenzymes; Isomerase; Lead; Localized Disease; Malignant neoplasm of prostate; Mediating; Neoplasm Metastasis; Operative Surgical Procedures; Public Health; Radiation; Recombinants; Resistance; Role; Second Primary Cancers; Series; Stanolone; Steroid biosynthesis; Steroids; Testing; Testosterone; United States; United States Food and Drug Administration; abiraterone; advanced disease; castration resistant prostate cancer; dehydroepiandrosterone; deprivation; docetaxel; effective therapy; improved; inhibitor/antagonist; men; oxidation; public health relevance; response; tumor; tumor progression

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.

描述（由申请人提供）：前列腺癌是美国男性癌症的最常见原因，也是癌症死亡的第二大原因。局部疾病可能通过放射线或手术可以治愈；但是，晚期疾病仍然无法治愈。性腺睾丸激素的耗竭是晚期疾病的前期标准疗法。不幸的是，转移性疾病几乎总是以cast割的前列腺癌（CRPC）的形式复发，这通常是这种疾病的致命形式。尽管性腺睾丸激素耗尽了，但CRPC仍由雄激素的肿瘤内合成驱动。阻止CYP17A1的阿比罗酮乙酸替代的生存益处是CRPC进展中雄激素合成必要性的最佳证据。最初或获得的对阿比特酮醋酸盐的抵抗是在2011年4月获得美国食品药品监督管理局（CRPC）治疗CRPC的，现已成为克服的下一个障碍。最近的研究表明，二氢睾丸激素（DHT）的合成是驱动CRPC进展的最有效的雄激素，意外地绕过睾丸激素。这一发现改变了潜在药物靶标的景观，并表明3？ - 羟基甾体脱氢酶/异构酶（3？hsd）是潜在的重要且可行的药理靶标。该提案的总体假设是，有效的3 hsd药理抑制作用将是对CRPC和对乙酸阿比罗酮具有抗性的有效治疗方法。在AIM 1中，将定义3？HSD1和3？HSD2表达CRPC的发展和进展的作用和要求。在AIM 2中，乙酸阿比罗酮的影响对3？HSD1和3？HSD2的转化为3？HSD2。在AIM 3中，将合成一系列类固醇副唑，并确定重组3？HSD1和3？HSD2的候选抑制剂，这也抑制CYP17A1。该提案的最终预期好处是开发了新的和改进的CRPC男性治疗方法。