Novel gene that determines metastatic phenotype in African-American men with PCa

决定非裔美国前列腺癌男性转移表型的新基因

基本信息

批准号：
9103022
负责人：
Mohammad Saleem Bhat
金额：
$ 17.32万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9103022
关键词：
Adhesions African African American Behavior Biological Markers Biopsy Caring Caucasians Cell Proliferation Cells Confocal Microscopy DOCK1 gene Data Development Diagnosis Diagnostic Neoplasm Staging Disease E-Cadherin Economics Employee Strikes Etiology Exhibits Failure Genes Growth Health Human Hypermethylation Immunoprecipitation In Vitro Indolent Investigation Knowledge Luciferases Malignant Neoplasms Malignant neoplasm of prostate Metastatic Prostate Cancer Modeling Molecular Neoplasm Metastasis Nude Mice Organogenesis Outcome Pathway interactions Patients Phenotype Play Population Primary Neoplasm Prostatic Tissue Protocols documentation Race Recurrence Reporter Reporting Reproductive system Retrospective Studies Role Signal Transduction Specimen Staging Techniques Testing Therapeutic Time Tissues Treatment Failure Tumor Suppressor Genes Tumor stage base carcinogenesis cell growth cell motility chemotherapy clinically relevant cohort disease phenotype disorder control effective therapy follow-up health disparity high risk in vitro Model in vivo Model men migration mortality mouse model mutant neoplastic cell novel potential biomarker predictive marker promoter prostate cancer cell racial disparity subcutaneous therapeutic target tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): 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.

描述：前列腺癌（CAP）被诊断出的最明显的种族差异，与高加索男性相比，cap死亡的风险高2-3倍。由于对转移性细胞生长和运动的机制的知识很少。肿瘤细胞 - 表型。我们表明，非洲人的原发性和指标之间的差异是可以区分的（而白种人患者表现CAP细胞T型高甲基化全球假设是，Robo1可以像潜在的生物标志物一样，在Primastatiticeaseaseaseasease Afr Ican-American男性之间取消，Robo1值得进一步调查使用Revant-Race，使用不同的体外和体内目标。＃1）：研究在非裔美国人中使用癌变D模型的cap发育阶段的机理作用-ROBO1作为（a）疾病表型触发的生物标志物和（b）非裔美国人的cap攻击。因为生物标志物将有助于临床治疗，如果患者可以接受治疗，并且对非洲裔美国人的患者有用。