Combating Highly Aggressive Prostate Cancer: Development of Novel Patient Derived Xenograft Models and Application in Preclinical Studies of Novel Selective Androgen Receptor Degraders

项目摘要 癌症发病率、患病率、死亡率和存活率的差异给少数族裔带来了负担 美国的人口。此外，这些少数群体在治疗临床中的代表性仍然很低。 审判。我们的少数民族患者衍生异种移植(PDX)开发和试验中心(M-PDTC)提供了独特的 这是帮助解决这些种族/族裔差距的机会。这个中心是建立在科学前提下的， 除了重要的社会经济因素外，健康差距给种族/少数民族造成了负担 美国与人们知之甚少的遗传和其他内在因素有关。我们建议利用 贝勒医学院(BCM)的大量少数族裔癌症患者，以产生和 利用不同种族/少数民族血统的创新PDX模式，这将有助于整个科学 社区描绘了种族/少数民族起源的癌症的分子基础。休斯顿是最多的 多种多样的美国大城市，约20%的居民是非洲裔美国人(AA)，约40%的居民是西班牙裔。BCM教职员工 负责为大量少数民族人口服务的两家主要教学医院的临床护理：Ben Taub 公立医院(BTH)(91%的患者是少数族裔)，以及Michael E.DeBakey VA医疗中心 (MEDVAMC)，美国最大的退伍军人医疗中心之一，为东南部超过10万名退伍军人提供服务 德克萨斯州(约30%为AA)。因此，有非常大的少数族裔癌症患者可供选择。 组织捐献。BCM在成功招募少数族裔患者进行临床试验方面有着长期的记录。 除了我们BCM的大量AA患者外，BTH的59%的患者是西班牙裔种族。我们有 组建了一个多学科、多机构的协作团队，汇聚了PDX模式的专家 世代、分子生物学和信号通路、动物药物治疗研究、病理学和临床 来自BCM和MD Anderson癌症中心(MDACC)的前列腺癌和乳腺癌的管理。我们是 非常适合利用我们机构的技术资源以及我们众多的种族和民族 为了支持M-PDTC RFA的更广泛目标，特别是 促进这些人口的生物量捐赠，增加这些人的种族和民族多样性 PDXNet癌症信息库，以及支持我们两项研究的具体目标 前列腺癌和乳腺癌的研究项目。如果有的话，很少有癌症中心有这种杰出的 研究基础，大量非裔美国人，西班牙裔和亚洲癌症患者，以及BCM的强劲轨迹 从我们的集水区(休斯敦)成功招募少数民族患者进入临床试验的记录。此外， 我们的两个研究项目将利用完整外显子组测序(WES)、全局RNA测序(RNA-SEQ)、 定量蛋白质组(QKiP)和代谢组谱，并将进行有前景的NCI-IND的临床前试验 在少数民族人群中发现新的、有效的前列腺癌和乳腺癌治疗策略的药物。

Project Summary Disparities in cancer incidence, prevalence, mortality and survivorship burden racial and ethnic minority populations in the US. In addition, these minority populations remain underrepresented in therapeutic clinical trials. Our Minority Patient-Derived Xenograft (PDX) Development and Trial Center (M-PDTC) provides a unique opportunity to help address these racial/ethnic disparities. This Center is built on the scientific premise that, in addition to important socioeconomic factors, health disparities that burden racial/ethnic minorities in the US are linked to poorly understood genetic and other intrinsic factors. We propose to leverage the high numbers of minority cancer patients at Baylor College of Medicine (BCM) in order to generate and utilize innovative PDX models of diverse racial/ethnic minority origin, which will assist the entire scientific community delineate the molecular underpinnings of cancer of racial/ethnic minority origin. Houston is the most diverse large US city, with ~20% of its residents being African American (AA) and ~40% Hispanic. BCM faculty are responsible for clinical care at two major teaching hospitals that serve large minority populations: Ben Taub Hospital (BTH), a public hospital (91% of patients are minorities), and the Michael E. DeBakey VA Medical Center (MEDVAMC), one of the largest VA Medical Centers in the US, which serves over 100,000 veterans in Southeast Texas (~30% are AA). Thus, there is a very large population of minority cancer patients available for potential tissue donations. BCM has a long track record of successfully enrolling minority patients in clinical trials. In addition to our large AA patient population at BCM, 59% of patients at BTH are of Hispanic ethnicity. We have assembled a multidisciplinary and multi-institutional collaborative team, bringing together experts in PDX model generation, molecular biology and signaling pathways, animal drug treatment studies, pathology and clinical management of prostate and breast cancer from BCM and MD Anderson Cancer Center (MDACC). We are ideally positioned to leverage the technical resources of our institutions and our high numbers of racial and ethnic minority cancer patients at BCM, in order to support the broader goals of the M-PDTC RFA, in particular to facilitate biospecimen donations from these populations and increase the racial and ethnic diversity of the PDXNet repository in a wide spectrum of cancers, as well as to support the Specific Aims of our two research projects in prostate and breast cancer. Few, if any, cancer centers have this combination of an outstanding research base, large numbers of African American, Hispanic and Asian cancer patients, and BCM’s robust track record of successfully enrolling minority patients from our catchment area (Houston) into clinical trials. Moreover, our two research projects will utilize whole exome sequencing (WES), global RNA-sequencing (RNA-seq), quantitative proteomic (qKiP) and metabolomic profiling and will conduct preclinical trials of promising NCI-IND drugs to uncover novel, effective treatment strategies for prostate and breast cancer in minority populations.