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

 描述(申请人提供)：前列腺癌(CAP)表现出最显著的种族差异，因为非裔美国人男性被诊断为CAP的风险是白人男性的1.4倍，死于CAP的风险是白人男性的2-3倍。患有转移性帽子的非裔美国人的死亡率很高。寻找治疗这种致命疾病的有效治疗方法的障碍是由于对转移细胞生长和运动的机制缺乏了解。我们已经确定了一种控制非裔美国人转移型肿瘤细胞生长和运动的新机制。我们提供了Robo1(回旋基因1)作为肿瘤抑制基因和决定肿瘤细胞表型命运的重要检验点的证据。在器官发生过程中，Robo1被报道调节包括生殖系统在内的组织中细胞的增殖、迁移和黏附。利用非洲裔美国人CAP患者的前列腺组织，以及非洲裔美国人CAP病的基于细胞的模型，我们表明，在非洲裔美国人的转移状态下，Robo1丢失。我们表明，在非裔美国人中，Robo1的表达水平在原发阶段和转移阶段之间是显著可区分的(而作为高加索人，患者在肿瘤阶段之间没有表现出这种差异)。此外，我们提供的证据表明，Robo1基因启动子在非裔美国人转移帽细胞中存在高甲基化，而高加索人转移帽细胞中没有表现出该基因的高甲基化。这些数据清楚地表明，Robo1是区分非洲裔美国人帽子和高加索人帽子的一个因素，并表明该基因在非裔美国人健康差距中可能起到了作用。我们的原理验证研究表明，Robo1的重新激活抑制了转移的肿瘤细胞的迁移，从而暗示了Robo1途径在CAP中的治疗潜力。基于这些数据，我们产生了一个全球假设，即Robo1可以作为一个潜在的生物标记物，区分非裔美国人的原发和转移性疾病。我们建议使用不同的体外和体内相关种族模型对Robo1进行进一步研究。我们提出了三个具体的目标：(目标1)：利用非裔美国人的致癌细胞模型，研究Robo1在帽子发育的进展阶段中基于机制的作用。(目的#2)：利用非裔美国人CAP皮下和原位小鼠模型，研究Robo1作为转移性肿瘤生长治疗靶点的意义。(目标3)：测试组织机器人1作为生物标记物在非裔美国人中作为(A)疾病表型区分和(B)帽子侵袭性的相关性。我们相信，这一建议的成功结果将在提供临床相关的表型区分生物标记物方面具有极其重要的价值。作为一种生物标志物，Robo1将帮助临床医生决定患者是否应该接受治疗，并将对非裔美国人患者有用。我们认为，Robo1是治疗非裔美国人转移性帽子疾病的可用药靶点。

 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.