Racial Disparities in the Mechanisms of Prostate Cancer Metastasis

Project Summary/Abstract Prostate cancer (PCa) is responsible for one of the greatest racial health disparities, with African-American (AA) men experiencing a death rate 2.4 times higher than that for EA men, which accounts for nearly 40% of the total overall cancer mortality disparity between AA and EA men. PCa mortality is largely due to metastases, and thus it is critical to understand the racial disparities in the mechanisms of metastasis in AA PCa. Our preliminary studies have shown that genes related to oxidative phosphorylation (OXPHOS) are enriched in PCa tumors from AA men relative to EA men, as well as between normal tissue, primary tumors, and LNM. FGFR3 is a fibroblast growth factor tyrosine kinase receptor that binds to fibroblast growth factor ligands and activates OXPHOS, PI3K/AKT, STAT, RAS/MAPK, and ERK signaling pathways. We have also discovered splice site mutations in FGFR3 that are present in both primary tumor foci and LNM and have shown that FGFR3 mutations are more frequent in metastases than primary tumors examining data from over 6500 samples. We have also determined that FGFR3 expression is significantly correlated with % African ancestry in TCGA patients, and we have identified three SNPs in the FGFR3 enhancer with >40% allele frequency differences in AA populations. Moreover, FGFR3 expression was significantly higher in our datasets of prostate tumors from AA men than from EA men. We hypothesize that the OXPHOS pathway and FGFR3 signaling play important roles in metastasis for AA men. We plan to test this hypothesis via the following Specific Aims: Aim 1. To analyze differential pathway activity in independent diverse patient cohorts. We hypothesize that FGFR3 and OXPHOS genes will be associated with African ancestry and metastasis. We will confirm and validate our preliminary findings examining prostatectomies, circulating tumor cell clusters, and metastatic biopsies. Aim 2. To analyze the impact of perturbation of FGFR3 signaling on metastasis using in vitro and in vivo models of AA prostate cancer. We hypothesize that increased FGFR3 expression and/or FGFR3 mutations may activate OXPHOS activity, promoting metastasis. We will investigate the mechanisms of disparities in regulation of FGFR3 expression and the impact of these novel mutations. Aim 3. To determine the effect of perturbation of OXPHOS on the metastatic potential of AA prostate cancer cell lines in vitro and in vivo. We hypothesize that OXPHOS activity promotes metastasis in AA PCa. We will manipulate OXPHOS activity to understand how it impacts metastasis in models of AA PCa. Completion of these studies will provide new insights into PCa metastasis in AA men, demonstrate the potential clinical utility of FGFR3 and/or OXPHOS inhibitors, and could ultimately help reduce cancer health disparities.