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

Prostate. 2020 Sep;80(13):1045-1057. doi: 10.1002/pros.24018. Epub 2020 Jul 20.

Abstract

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.

Keywords: African American; DECIPHER; DOCK1; ROBO1; prostate cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • African Americans / genetics*
  • Animals
  • Cell Line, Tumor
  • DNA Methylation
  • Health Status Disparities
  • Humans
  • Immunohistochemistry
  • Male
  • Neoplasm Metastasis
  • Nerve Tissue Proteins / biosynthesis
  • Nerve Tissue Proteins / deficiency
  • Nerve Tissue Proteins / genetics*
  • Promoter Regions, Genetic
  • Prostatectomy
  • Prostatic Neoplasms / ethnology*
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms / surgery
  • Receptors, Immunologic / biosynthesis
  • Receptors, Immunologic / deficiency
  • Receptors, Immunologic / genetics*
  • Whites / genetics
  • Zebrafish
  • rac GTP-Binding Proteins / antagonists & inhibitors
  • rac GTP-Binding Proteins / genetics*
  • rac GTP-Binding Proteins / metabolism
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism

Substances

  • DOCK1 protein, human
  • Nerve Tissue Proteins
  • RAC1 protein, human
  • Receptors, Immunologic
  • roundabout protein
  • rac GTP-Binding Proteins
  • rac1 GTP-Binding Protein