Abstract 5014: Identifying and treating robo<i>1−ve/dock1+ve</i> prostate cancer: An aggressive cancer type highly prevalent in African-American patients
Authors: Marina Graciela Ferrari, Arsheed Ganaie, Adrian P. Mansini, Mohammad Saleem
Journal: Cancer Research (2020)

Abstract Grant Funding: R01CA193739 Metastasis is the principal cause of death in prostate cancer (CaP) patients. The prognosis is very poor for metastatic CaP. On comparison, African-American patients exhibit high mortality rates than Caucasian counterparts. The failure of therapies for metastatic CaP is observed very high in patients belonging to African-American race. There is a need to identify new target-based therapies which could be either (i) beneficial to patients regardless of race or (ii) treat high-risk patients such as African-Americans who fail standard therapies compared to Caucasians. This requires identification of molecular pathways which are either (i) preferentially active in African-Americans or (ii) highly active in both races. We posit that the loss of ROBO1 in advanced stage CaP contributes to the disparity observed between African-Americans and Caucasian. We conducted a comprehensive analysis of race-based primary and metastatic tumors for ROBO1 and its downstream targets (RAC1, DOCK1, E-Cadherin, and β-catenin). We show that ROBO1 expression is progressively lost with the increasing stage of CaP in African-American patients. Next, in order to explore the underlying mechanism that leads to ROBO1 loss, we analyzed matching tumor DNA from patients and found that the ROBO1 promoter is methylated in the majority of African-American cases in agreement with the CaP stage. In addition, we found that ROBO1 loss is associated to increasing RAC1 activation in tumors and representative cell models. We show that loss of ROBO1 results in increased DOCK1 activity that in turn induces Rac1 signaling in CaP cells. We hypothesized that targeting DOCK1/Rac1 network could be an ideal strategy to treat metastatic CaP, particularly in ROBO1−/- cases. To test the hypothesis, we tested the therapeutic efficacy of a selective inhibitor of DOCK1/Rac1 interaction in ROBO1+ve and ROBO1−ve CaP cells. We observed that DOCK1-inhibitor treatment significantly decreased the RAC1 activation and β-catenin activity in metastatic CaP cells. Notably, inhibition of DOCK1/Rac1 was observed to significantly decrease the motility and invasiveness of aggressive metastatic CaP cells. Furthermore, DOCK1-inhibitor significantly blocked the potential of metastatic CaP cells to extravasate (cross-over) through the endothelial lining (constituted of HUVEC cells). These data suggested the significance of DOCK1/Rac1 pathway in a metastasis of CaP particularly in African-Americans. We conclude that the ROBO1/RAC1 ratio in tumor biopsies could be developed as an early biomarker of metastasis in African-American patients. We suggest that DOCK1-inhibitor therapy would be more beneficial to patients who exhibit ROBO1− tumor, and African-American patients are such as group who likely to benefit this therapy. Citation Format: Marina Graciela Ferrari, Arsheed Ganaie, Adrian P. Mansini. Identifying and treating robo1−ve/dock1+ve prostate cancer: An aggressive cancer type highly prevalent in African-American patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5014.