Compensatory steroidogenesis mechanisms in 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非皮肤恶性肿瘤和第二大癌症死亡原因，因此是一个主要的公共卫生问题。局限性疾病是高度可治疗的;然而，转移性前列腺癌仍然无法治愈。 通过药物或手术去势的雄激素剥夺治疗（ADT）是晚期前列腺癌的前期标准治疗。虽然最初有效，但肿瘤对ADT产生耐药性，这种疾病称为去势抵抗性前列腺癌（CRPC）。已经清楚的是，CRPC在很大程度上是由双氢睾酮（DHT）的肿瘤内合成驱动的，这允许雄激素受体（AR）的重新接合。CRPC对DHT的依赖性部分由雄激素合成抑制剂阿比特龙的临床疗效证明。然而，诱导DHT合成的代谢机制尚未阐明。我们最近在一种类固醇生成酶中发现了第一个功能获得性突变，这种酶负责增加DHT的合成和CRPC的发展。3羟类固醇脱氢酶-1（3 D1）的这种突变阻断了泛素化，增加了稳态酶水平，并加速了前体类固醇的代谢通量，否则这是DHT合成的限速步骤。然而，这种突变存在于少数患者的CRPC肿瘤中;因此，必须阐明其他促进3-D酶活性，DHT合成，并允许在缺乏突变体3-D1的情况下发展CRPC的变化。 我们的总体假设是，替代机制阻断野生型3-D1泛素化，稳定蛋白水平，并补偿突变型3-D1的缺失，不仅在CRPC模型中，而且在临床肿瘤中。我们目前的建议将确定在缺乏突变体3-D1的情况下发生的类固醇合成的补偿机制。在目标1中，我们将确定当野生型3 β D1存在时，泛素E3连接酶AMFR的表达是否受到抑制。 此外，我们将确定AMFR如何调节DHT的合成，雄激素反应和CRPC的发展。在目标2中，我们将确定CRPC患者肿瘤中AMFR失调的临床相关性，以及阿比特龙初治和阿比特龙耐药的匹配临床肿瘤。总之，这些研究将确定和临床验证类固醇合成的补偿机制，绕过3-D1突变。预计这项工作将导致识别治疗反应的生物标志物，并确定CRPC的新治疗方式，因此将产生广泛和潜在的快速临床影响。

DESCRIPTION (provided by applicant: Prostate cancer is the most common non-skin malignancy and second leading cause of cancer death for men in the United States and is therefore a major public health problem. Localized disease is highly treatable; metastatic prostate cancer, however, remains incurable. Androgen deprivation therapy (ADT) by means of medical or surgical castration is the upfront standard treatment for advanced prostate cancer. Although initially effective, tumors become resistant to ADT, a disease state termed castration-resistant prostate cancer (CRPC). It has become clear that CRPC is driven in large part by the intratumoral synthesis of dihydrotestosterone (DHT), which permits a reengagement of the androgen receptor (AR). The dependence of CRPC on DHT is evidenced in part by the clinical efficacy of the androgen synthesis inhibitor, abiraterone. However, the metabolic mechanisms that induce DHT synthesis have not been elucidated. We have recently identified the first gain-of-function mutation in a steroidogenic enzyme that is responsible for increasing DHT synthesis and the development of CRPC. This mutation in 3�ydroxysteroid dehydrogenase-1 (3�D1) blocks ubiquitination, increasing steady-state enzyme levels and hastens metabolic flux from precursor steroids in what is otherwise the rate-limiting step for DHT synthesis. However, the mutation is present in a minority of CRPC tumors from patients; consequently, other changes that promote 3�D enzymatic activity, DHT synthesis, and permit the development of CRPC in the absence of mutant 3�D1 must be elucidated. Our overarching hypothesis is that alternative mechanisms block wild-type 3�D1 ubiquitination, stabilize protein levels and compensate for the absence of mutant 3�D1, not only in CRPC models but also clinical tumors. Our current proposal will identify compensatory mechanisms of steroidogenesis that occur in the absence of mutant 3�D1. In Aim 1, we will identify whether expression of the ubiquitin E3-ligase, AMFR, is suppressed when wild-type 3�D1 is present. Furthermore, we will determine how AMFR regulates DHT synthesis, the androgen response and development of CRPC. In Aim 2, we will define the clinical relevance of AMFR dysregulation in tumors from patients with CRPC, as well as matched clinical tumors that are abiraterone-na�ve and abiraterone-resistant. Together, these studies will identify and clinically validate compensatory mechanisms of steroidogenesis that circumvent the mutation in 3�D1. It is anticipated that this work will lead to the identification of biomarkers of treatment response and identify new treatment modalities for CRPC and thus will have a broad and potentially rapid clinical impact.