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 of ROBO1-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 that ROBO1 is lost during the progressive stages of CaP, a prevalent feature in African-Americans. We show that the loss of ROBO1 predicts high-risk of recurrence, metastasis and poor outcome of androgen-deprivation therapy in radical prostatectomy-treated patients. These data identified an aggressive ROBO1deficient/DOCK1+ve sub-class of CaP. Combined genetic and IHC data showed that ROBO1 loss is accompanied by DOCK1/Rac1 elevation in grade-III/IV primary-tumors and Mets. We observed that the hypermethylation of ROBO1-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 treat ROBO1deficient metastatic-CaP. We tested the pharmacological efficacy of CPYPP, a selective inhibitor of DOCK1 under in vitro and in vivo conditions. Using ROBO1−ve and ROBO1+ve CaP models, we determined the median effective concentration of CPYPP for growth. DOCK1-inhibitor treatment significantly decreased the (a) Rac1-GTP/β-catenin activity, (b) transmigration of ROBO1deficient cells across endothelial lining, and (c) metastatic spread of ROBO1deficient cells through the vasculature of transgenicfl Zebrafish model. Conclusion: We suggest that ROBO1 status 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.
Bibliographical noteFunding Information:
This study was supported by the US PHS grants (CA184685, and CA184685-02S1, CA193739 CHAAMP-pilot project of U54MD008620) to coauthor (MS). B.R. Konety is supported by US PHS grant (U54MD008620-06) and DOD grant (W81XWH-17-1-0462). The authors?thank the PCBN supported by the DOD-grants (W81XWH-14-2-0182, W81XWH-15-2-0062) for providing RNA/DNA and race-disparity TMA's.
This study was supported by the US PHS grants (CA184685, and CA184685‐02S1, CA193739 CHAAMP‐pilot project of U54MD008620) to coauthor (MS). B.R. Konety is supported by US PHS grant (U54MD008620‐06) and DOD grant (W81XWH‐17‐1‐0462). The authors thank the PCBN supported by the DOD‐grants (W81XWH‐14‐2‐0182, W81XWH‐15‐2‐0062) for providing RNA/DNA and race‐disparity TMA's.
© 2020 Wiley Periodicals LLC
- African American
- prostate cancer