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

 描述（由申请人提供）：前列腺癌（CaP）表现出最显著的种族差异，因为与白人男性相比，非洲裔美国男性被诊断为CaP的风险高1.4倍，死亡风险高2-3倍。患有转移性CaP的非裔美国男性表现出高死亡率。确定治疗这种致命疾病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了解很少。我们已经确定了一种新的机制，控制非洲裔美国人转移型肿瘤细胞的生长和运动。我们提供的证据表明，ROBO 1（roundabout gene 1）作为一个抑癌基因和重要的检查点，决定肿瘤细胞表型的命运。在器官形成过程中，ROBO 1被报道调节包括生殖系统在内的组织中的细胞增殖、迁移和粘附。使用来自非洲裔美国人CaP患者的前列腺组织和代表非洲裔美国人CaP疾病的基于细胞的模型，我们表明ROBO 1在非洲裔美国人转移性疾病中丢失。我们发现，在非裔美国人中，原发性和转移性阶段之间ROBO 1表达水平的差异是显著可区分的（而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，ROBO 1基因启动子在非洲裔美国人转移性CaP细胞中是高甲基化的，而高加索人转移性CaP细胞没有表现出该基因的高甲基化。这些数据清楚地确立了ROBO 1作为区分非洲裔美国人CaP与高加索人CaP的一个因素，并表明该基因在非洲裔美国人健康差异中可能发挥的作用。我们的原理验证研究表明，ROBO 1的再激活抑制了转移性肿瘤细胞的迁移，从而表明了ROBO 1途径在CaP中的治疗潜力。基于这些数据，我们提出了一个全球性的假设，即ROBO 1可以作为一种潜在的生物标志物，区分非洲裔美国男性的原发性和转移性疾病。我们建议，ROBO 1值得进一步调查使用相关种族不同的体外和体内模型。我们提出了三个具体的目标：（目标#1）：研究机制为基础的作用ROBO 1在进行性阶段的CaP发展使用致癌细胞为基础的模型在非洲裔美国人。(Aim#2）：使用非裔美国人CaP的皮下和原位小鼠模型研究ROBO 1作为转移性肿瘤生长的治疗靶点的意义。(Aim#3）：测试组织-ROBO 1作为非裔美国人中（A）疾病表型-区别和（B）CaP-侵袭性的生物标志物的相关性。我们相信，该提案的成功结果对于提供临床相关的表型区分生物标志物将非常有价值。ROBO 1作为生物标志物将帮助临床医生决定患者是否应该接受治疗，并将对非洲裔美国患者有用。我们认为ROBO 1是治疗非裔美国男性转移性CaP疾病的药物靶点。

 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.