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（由适用提供）：前列腺癌（CAP）表现出最引人注目的种族差异，因为与高加索男性相比，非洲裔美国男性被诊断出诊断的风险高1.4倍，而死亡的CAP的风险高2-3倍。具有转移性帽的非洲裔美国男性的死亡率很高。识别有效治疗这种致命状况的有效治疗方法的障碍是由于对转移性细胞生长和运动机制的知识的匮乏所致。我们已经确定了一种新的机制，该机制控制着非裔美国人男性转移性肿瘤细胞的生长和运动。我们提供的证据表明，Robo1（回旋处基因1）充当肿瘤抑制基因，并且重要的检查点可以决定肿瘤细胞 - 表型的命运。在器官发生过程中，据报道ROBO1调节包括生殖系统在内的组织中的细胞增殖，迁移和粘合剂。使用来自非裔美国人CAP患者的前列腺组织，以及代表非裔美国人男性帽疾病的基于细胞的模型，我们表明ROBO1在非裔美国人男性的转移状态下丢失。我们表明，非洲裔美国人的原发性和转移阶段之间的ROBO1表达水平的差异是显着区别的（而由于高加索人患者在肿瘤阶段之间没有任何此类衰竭）。此外，我们提供了证据表明，在非裔美国人转移性CAP细胞中，Robo1基因启动子是高甲基化的，而高加索转移性CAP细胞不存在该基因的高甲基化。这些数据清楚地将ROBO1确定为将非裔美国人帽与白种人cap区分开的因素，并提出该基因在非裔美国人中健康差异中的可能作用。我们的原理证明研究表明，ROBO1的重新激活抑制转移性肿瘤细胞的迁移，因此表明Robo1-Pathway在CAP中具有治疗潜力。基于这些数据，我们产生了一个全球假设，即Robo1可以作为一种潜在的生物标志物，可以区分非裔美国人男性的原发性和转移性疾病。我们建议ROBO1需要使用不同的体外和体内模型的相关竞赛进行进一步研究。提案三个具体目的：（目标＃1）：使用基于癌变细胞的模型在非裔美国人中研究ROBO1在CAP发育的渐进阶段中基于机制的作用。（AIM＃2）：使用非裔美国人帽的皮下和原位小鼠模型来研究Robo1作为转移性肿瘤生长的治疗靶标的意义。（AIM＃3）：测试组织-ROBO1作为（a）疾病表型 - 触发和（b）在非裔美国人中的帽粘附性的生物标志物的相关性。我们认为，该提案的成功结果对于提供与临床相关的表型与生物标志物相关的结果将非常有价值。 ROBO1作为生物标志物将帮助临床医生确定患者是否应该接受治疗，对非裔美国人患者有用。我们建议ROBO1是在非洲裔美国男性中治疗转移性cap疾病的可吸毒靶标。