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.
Prostate cancer and its aggressive form castration-resistant prostate cancer (CRPC) are more prevalent and aggressive in African American men than in Caucasian men. African American men with prostate cancer have shorter progressive-free and overall survival than Caucasian American men. In this proposal, the expression and function of androgen receptor splice variants (AR-SVs) will be evaluated to test the hypothesis that higher AR SV expression is responsible for the aggressive CRPC phenotype in African American men.
