Racial Disparity in the Expression of Androgen Receptor Splice Variants (AR-SVs) in Prostate Cancer

在美国，大约174，000名男性被诊断患有前列腺癌（PCa）， 2019年有3.1万人死于PCa。预计PCa幸存者的数量将从目前的330万人增加到2010年的330万人。 到2026年达到450万。治疗失败和去势抵抗性前列腺癌的主要原因之一 CRPC复发是缺乏配体结合的组成型活性AR剪接变体（AR-SV）的表达， 结构域（LBD），从而保持组成型活性。AR-SV有助于CRPC的侵袭性表型， 较短的无进展生存期（PFS），以及对恩杂鲁胺或阿比特龙无应答。相比 高加索男性、非洲裔美国男性的总体PCa发病率高出63%（228.8 vs 140.3/100，000， 年龄调整为2000年美国人口）。这些患者更有可能被诊断为侵袭性/潜在性 致死性PCa的患者死于PCa的可能性高2.44倍，并且无病生存期较短。我们的中央 一种假设是，非洲裔美国男性中侵袭性CRPC的发病率较高是由于 AR-SV的表达和功能与其高加索人对应物相比。因为我们的SARD是唯一 一组具有降解AR-SV特性的分子，证明这一假设将有助于我们调整我们的 针对可能具有较高AR-SV表达的非洲裔美国男性的药物开发方案。 为了解决非洲裔美国人男性表达AR-SV的水平高于白人的假设， 在男性中，我们将确定AR-V7在来自非洲裔美国人的PCa和CRPC标本中的表达， 高加索男性（具体目标-1），通过量化AR-V7靶基因来确定AR-V7功能的种族差异 在来自非裔美国人和高加索人PCa患者PCa组织中的标记表达（特异性目标-2），以及测试 SARD在CRPC患者来源的异种移植物UT-1335中的疗效，该移植物从非洲裔美国人获得 人（具体目标-3）。这些数据将成为未来针对非洲裔美国人的药物开发的预兆 有PCa的人

Approximately 174,000 men in the United States were diagnosed with prostate cancer (PCa) and approximately 31,000 died of PCa in 2019. The number of PCa survivors is expected to increase from 3.3 million men currently to 4.5 million by 2026. One of the primary reasons for treatment failure and castration-resistant prostate cancer (CRPC) relapse is expression of constitutively-active AR splice variants (AR-SVs) that lack the ligand binding domain (LBD) and thus remain constitutively active. AR-SVs contribute to an aggressive phenotype of CRPC, shorter progression-free survival (PFS), and failure to respond to enzalutamide or abiraterone. Compared to Caucasian men, African American men have a 63% higher overall PCa incidence (228.8 vs 140.3 per 100,000, age adjusted to 2000 US population). These patients are more likely to be diagnosed with aggressive/potentially lethal PCa, are 2.44-fold more likely to die from PCa and have shorter disease-free survival. Our central hypothesis is that the higher incidence of aggressive CRPC in African American men is due to the higher expression and function of AR-SVs compared to their Caucasian counterparts. As our SARDs are the only set of molecules having the properties to degrade the AR-SVs, proving this hypothesis will help us to tailor our drug development protocols towards the African American men who might have higher expression of AR-SVs. To address the hypothesis that the African American men express AR-SVs at a higher level than Caucasian men, we will determine the expression of AR-V7 in PCa and CRPC specimens from African American and Caucasian men (specific aim-1), determine race differences in AR-V7 function by quantifying AR-V7-target gene signature expression in PCa tissue from African American and Caucasian PCa patients (specific aim-2), and test the efficacy of SARDs in CRPC patient-derived xenograft UT-1335 that was obtained from an African American man (specific aim-3). The data will be a harbinger for future drug development tailored towards African American men with PCa.