Identifying and treating ROBO1 -ve /DOCK1 +ve prostate cancer: An aggressive cancer subtype prevalent in African American patients.

Background There is a need to develop novel therapies which could be beneficial to patients with prostate cancer (CaP) including those who are predisposed to poor outcome, such as African-Americans. This study investigates the role ofROBO1-pathway in predicting outcome and race-based disparity in patients with CaP. Methods and Results Aided by RNA sequencing-based DECIPHER-testing and immunohistochemical (IHC) analysis of tumors we show thatROBO1is lost during the progressive stages of CaP, a prevalent feature in African-Americans. We show that the loss ofROBO1predicts high-risk of recurrence, metastasis and poor outcome of androgen-deprivation therapy in radical prostatectomy-treated patients. These data identified an aggressiveROBO1(deficient)/DOCK1(+ve)sub-class of CaP. Combined genetic and IHC data showed thatROBO1loss is accompanied byDOCK1/Rac1elevation in grade-III/IV primary-tumors and Mets. We observed that the hypermethylation ofROBO1-promoter contributes to loss of expression that is highly prevalent in African-Americans. Because of limitations in restoring ROBO1 function, we asked if targeting the DOCK1 could be an ideal strategy to inhibit progression or treatROBO1(deficient)metastatic-CaP. We tested the pharmacological efficacy of CPYPP, a selective inhibitor of DOCK1 under in vitro and in vivo conditions. UsingROBO1(-ve)andROBO1(+ve)CaP models, we determined the median effective concentration of CPYPP for growth. DOCK1-inhibitor treatment significantly decreased the (a) Rac1-GTP/beta-catenin activity, (b) transmigration ofROBO1(deficient)cells across endothelial lining, and (c) metastatic spread ofROBO1(deficient)cells through the vasculature of transgenic(fl)Zebrafish model. Conclusion We suggest thatROBO1status forms as predictive biomarker of outcome in high-risk populations such as African-Americans and DOCK1-targeting therapy has a clinical potential for treating metastatic-CaP.