Prostate cancer (CaP) exhibits the most striking racial disparity, as African American men are at 1.4 times higher risk of being diagnosed and 2-3 times higher risk of dying of CaP, compared to Caucasian men. African- American men with metastatic-CaP exhibit a high rate of mortality. The impediment in identifying an effective treatment to treat this lethal condition is due to the paucity in the knowledge about the mechanism of metastatic cell growth and motility. We have identified a novel mechanism that controls growth and motility of metastatic-type tumor cells in African-American men. We provide evidence that ROBO1 (roundabout gene 1) acts as a tumor suppressor gene and important check-point that decides the fate of tumor cell-phenotype. During organogenesis, the ROBO1 is reported to regulate cell proliferation, migration and adhesion in tissues including reproductive system. Using prostatic tissues from African-American CaP patients, and cell-based model representative of CaP disease in African-American men, we show that ROBO1 is lost during metastatic condition in African-American men. We show that the difference in ROBO1 expression levels between primary and metastatic stage in African-Americans is significantly distinguishable, (while as Caucasians patients exhibit none of such distinctions between tumor stages). Furthermore, we provide evidence that ROBO1 gene- promoter is hypermethylated in African-American metastatic-CaP cells, whereas Caucasian metastatic-CaP cells do not exhibit hypermethylation of this gene. These data clearly establishes ROBO1 as a factor that distinguishes African-American CaP from Caucasian-CaP, and suggests a possible role of this gene in health disparity in African-Americans. Our proof-of principle studies showed that reactivation of ROBO1 inhibits the migration of metastatic tumor cells thus suggesting the therapeutic potential of ROBO1-pathway in CaP. Based on these data, we generated a global hypothesis that ROBO1 could act as a potential biomarker that would discriminate between primary and metastatic disease in African-American men. We suggest that ROBO1 warrants further investigation using relevant-race distinct in vitro and in vivo models. We propose three specific aims:
(Aim# 1): To study the mechanism-based role of ROBO1 during the progressive stages of CaP development using a carcinogenesis cell-based model in African-American men.
(Aim #2) : To investigate the significance of ROBO1 as a therapeutic target for metastatic tumor growth using subcutaneous and orthotopic mouse models of African-American CaP.
(Aim#3) : Test the relevance of tissue-ROBO1 as a biomarker for (A) disease phenotype-distinction and (B) CaP-aggressiveness in African-Americans. We believe that the successful outcome of this proposal will be extremely valuable in providing a clinically relevant phenotype- distinguishing biomarker. ROBO1 as a biomarker would help clinicians to decide if a patient should go for therapy and will be useful for African-American patients. We suggest that ROBO1 is a druggable target for treating metastatic-CaP disease in African-American men.
Prostate cancer exhibits the most striking racial disparity and African-American men with metastatic prostate cancer exhibit a high rate of mortality. This proposal will be valuable in providing a (A) novel predictive biomarker and (B) druggable target for treating prostate cancer disease in African-American men.
| Ganaie, Arsheed A; Beigh, Firdous H; Astone, Matteo et al. (2018) BMI1 Drives Metastasis of Prostate Cancer in Caucasian and African-American Men and Is A Potential Therapeutic Target: Hypothesis Tested in Race-specific Models. Clin Cancer Res 24:6421-6432 |
