Elucidating a novel molecular biomarker for castration-resistant 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。通过消耗性腺睾酮的雄激素剥夺疗法是晚期疾病的前期标准疗法。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，这是这种疾病的致命形式。现在清楚的是，CRPC仍然由雄激素的肿瘤内合成驱动，尽管血清睾酮耗尽。醋酸阿比特龙可阻断CYP 17 A1，2011年4月被美国食品药品监督管理局批准用于治疗CRPC，其带来的生存获益是CRPC进展中雄激素合成必要性的最佳证据。尽管大多数CRPC患者对醋酸阿比特龙有反应，但一个亚组没有任何初始反应，几乎所有有反应的肿瘤最终都会获得耐药性。最近一项经临床验证的发现表明，从肾上腺前体类固醇转化为双氢睾酮（DHT）（驱动CRPC进展的最有效的雄激素）意外地绕过睾酮。这一发现改变了目前的工作模型，并表明3 <$$>-羟基类固醇脱氢酶/异构酶（3 <$HSD）是调节DHT合成和CRPC发展的关键点。该提议的首要假设是，在CRPC病例的一个子集的发展中，体细胞功能获得性突变发生在3 <$HSD1中，增加突变酶的稳定性，增强DHT合成并赋予对醋酸阿比特龙的抗性。在目标1中，将进行一项初步临床研究，以确定携带野生型和突变型3 <$HSD1的CRPC肿瘤如何调节向DHT的通量并对醋酸阿比特龙作出反应。在目标2中，将评估突变体3 <$HSD1作为潜在药理学靶标的有效性。在目标3中，将评估野生型和突变型3 <$HSD1相互作用的后果。该提案的最终预期受益是鉴定CRPC中类固醇生成酶中的首个功能获得性突变，其可作为对激素治疗（包括醋酸阿比特龙）的反应或耐药性的生物标志物。此外，预计分别与肺癌和黑色素瘤中的EGFR和BRAF突变相似，这项工作将验证突变体3 <$HSD1作为CRPC治疗的药理学靶点。

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. Androgen deprivation therapy by depletion of gonadal testosterone is the upfront standard therapy for advanced disease. Metastatic disease almost invariably recurs as castration-resistant prostate cancer (CRPC), which is the lethal form of this disease. It is now clear that CRPC remains driven by the intratumoral synthesis of androgens, despite the depletion of serum testosterone. The survival benefit conferred by abiraterone acetate, which blocks CYP17A1 and was approved by the United States Food and Drug Administration in April 2011 for the treatment of CRPC, is the best evidence for the necessity of androgen synthesis in the progression of CRPC. Although the majority of patients with CRPC respond to abiraterone acetate, a subset do not have any initial response and nearly all responding tumors will eventually acquire resistance. A recent discovery that has been clinically validated has demonstrated that conversion from adrenal precursor steroids to dihydrotestosterone (DHT), the most potent androgen that drives CRPC progression, unexpectedly bypasses testosterone. This finding alters the current working model and suggests that 3¿-hydroxysteroid dehydrogenase/isomerase (3¿HSD) is a critical point of regulation in the synthesis of DHT and development of CRPC. The overarching hypothesis of this proposal is that a somatic gain-of-function mutation occurs in 3¿HSD1 in the development of a subset of CRPC cases, increases mutant enzyme stability, augments DHT synthesis and confers resistance to abiraterone acetate. In Aim 1, a pilot clinical study will be undertaken to determine how CRPC tumors harboring wild-type and mutant 3¿HSD1 regulate flux to DHT and respond to abiraterone acetate. In Aim 2, the validity of mutant 3¿HSD1 as a potential pharmacologic target will be assessed. In Aim 3, the consequences of wild-type and mutant 3¿HSD1 interaction will be assessed. The ultimate anticipated benefit of this proposal is the identification of a first-in-clas gain-of-function mutation in a steroidogenic enzyme in CRPC that may serve as a biomarker of response or resistance to hormonal therapies, including abiraterone acetate. Furthermore, it is anticipated that similar to EGFR and BRAF mutations in lung cancer and melanoma, respectively, this work will validate mutant 3¿HSD1 as a pharmacologic target for therapy in CRPC.