Compensatory steroidogenesis mechanisms in castration-resistant prostate cancer

描述（由申请人提供）：前列腺癌是美国最常见的非皮肤恶性肿瘤，也是男性癌症死亡的第二大原因，因此是一个主要的公共卫生问题。局部疾病是高度可治疗的；然而，转移性前列腺癌仍然无法治愈。雄激素剥夺疗法（ADT）通过药物或手术阉割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，这种疾病状态称为去势抵抗性前列腺癌（CRPC）。很明显，CRPC在很大程度上是由肿瘤内双氢睾酮（DHT）的合成驱动的，DHT允许雄激素受体（AR）的再接合。雄激素合成抑制剂阿比特龙的临床疗效部分证明了CRPC对DHT的依赖性。然而，诱导DHT合成的代谢机制尚未阐明。我们最近发现了第一个甾体生成酶的功能获得突变，该酶负责增加DHT的合成和CRPC的发展。3′羟基类固醇脱氢酶-1（3′D1）的突变阻断了泛素化，增加了稳态酶水平，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，这种突变存在于来自患者的少数CRPC肿瘤中；因此，必须阐明其他促进3 - D酶活性、DHT合成和在没有突变体3 - D1的情况下允许CRPC发育的变化。我们的总体假设是，不仅在CRPC模型中，而且在临床肿瘤中，其他机制阻断了野生型3 - D1泛素化，稳定了蛋白质水平，并补偿了突变型3 - D1的缺失。我们目前的建议是确定在没有突变体3d1的情况下甾体生成的补偿机制。在Aim 1中，我们将确定当野生型3 α 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合成，雄激素反应和CRPC的发展。在Aim 2中，我们将定义CRPC患者肿瘤中AMFR失调的临床相关性，以及匹配的阿比特龙阴性和阿比特龙耐药的临床肿瘤。总之，这些研究将确定和临床验证规避3d1突变的类固醇生成的代偿机制。预计这项工作将导致鉴定治疗反应的生物标志物，并确定CRPC的新治疗模式，因此将具有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.