The ODC A allele as a driver and therapeutic target of aggressive prostate cancer in African American men

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Project Summary The rates of prostate cancer (PCa) incidence and mortality are much higher in African American men (AAM) versus European American men (EAM), and genetic variations between these races play a critical role. Our studies have shown that expression of genes that direct polyamine biosynthesis are significantly elevated in AAM versus EAM PCa, suggesting this pathway may play important roles in driving this cancer health disparity. Ornithine decarboxylase (ODC) is the first and rate-limiting enzyme of polyamine biosynthesis. Notably, the ODC gene has a single nucleotide polymorphism (SNP) at base +316 in which adenine (A) is substituted for guanine (G), and this SNP augments ODC promoter activity. Importantly, the ODC A allele is more common in AAM than EAM, suggesting prostate tumors in AAM having an ODC A allele will have increased ODC levels and that this drives aggressive prostate tumor biology. Furthermore, difluoromethylornithine (DFMO), a selective ODC inhibitor, is a highly effective chemoprevention agent in high-risk men harboring at least one ODC A allele, suggesting the ODC A allele will predict AAM PCa patients that benefit from DFMO treatment. These data support our hypothesis that the ODC A allele is both a driver of aggressive prostate tumor biology and a targetable vulnerability in African American men. To test this hypothesis, in Aim 1 we will use an allelic discrimination assay to test ~3,800 DNA samples (~1,520 AAM: ~2,280 EAM) from PCa cases and controls for the presence of the ODC A allele to: (i) establish its frequency in both races; and (ii) assess if the ODC A allele connotes worse patient outcomes. In Aim 2, we will generate three sets of isogenic PCa cell lines by CRISPR-based prime editing, where we will test if PCa cells with an ODC A allele have increased levels of ODC and polyamines and have more aggressive biological phenotypes compared to isogenic PCa cells with ODC G alleles. In Aim 3, we will test if treatment of our isogenic cells with DFMO and a polyamine transport inhibitor (polyamine blockage therapy) has differential effects on the phenotypes of PCa cells having ODC A versus ODC G alleles. Finally, we will also test if there are differential effects of polyamine blocking therapy on primary PCa tissue explants from AAM having an ODC A allele versus AAM with only ODC G alleles. We submit the proposed studies will benefit African American PCa patients by establishing the ODC A allele as a prognostic biomarker that will be useful for doctors to assess patient risk, and as a predictive biomarker that forecasts the success of DFMO as a chemotherapeutic treatment.