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

对抗高度侵袭性前列腺癌：新型患者异种移植模型的开发及其在新型选择性雄激素受体降解剂临床前研究中的应用

• 批准号: 10435884
• 负责人: Nicholas Mitsiades
• 金额: $ 12万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10435884
• 关键词: Address; African American; Androgen Receptor; Animals; Area; Asians; Breast; Cancer Burden; Cancer Center; Cancer Patient; Carboplatin; Catchment Area; Caucasians; Cities; Clinical Management; Clinical Trials; Collection; Communities; Comprehensive Cancer Center; DNA Repair; Development; Endocrine; Enrollment; Estrogen Receptors; Estrogen receptor positive; Ethnic Origin; Ethnic group; Excess Mortality; Faculty; Funding; Generations; Genetic; Genome; Goals; Hispanic Americans; Hispanics; Hospitals; Incidence; Institution; International; Intrinsic factor; Latino; Lead; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Medical Oncologist; Medical center; Medicine; Minority; Minority Groups; Molecular; Molecular Biology; Network-based; Organoids; Pathologist; Pathology; Patient-derived xenograft models of breast cancer; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phosphotransferases; Physicians; Population; Positioning Attribute; Prevalence; Proteome; Proteomics; Public Hospitals; Research; Research Project Grants; Resistance; Resources; Role; Scientist; Signal Pathway; Signal Transduction; Socioeconomic Factors; Teaching Hospitals; Texas; Therapeutic Clinical Trial; Tissue Donations; Translational Research; Veterans; Woman; base; cancer clinical trial; cancer health disparity; caucasian American; clinical care; college; combinatorial; effective therapy; ethnic diversity; ethnic minority population; exome sequencing; experience; health disparity; in vivo Model; inhibitor/antagonist; innovation; malignant breast neoplasm; men; metabolome; metabolomics; molecular oncology; mortality; multidisciplinary; novel; patient derived xenograft model; patient population; preclinical study; preclinical trial; programs; prostate cancer model; proteogenomics; racial and ethnic; racial and ethnic disparities; racial diversity; racial health disparity; racial minority; repository; response; survivorship; transcriptome; transcriptome sequencing; treatment strategy

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.

项目摘要 癌症发病率、流行率、死亡率和存活率的差异给少数种族和族裔造成负担 美国的人口。此外，这些少数群体在治疗性临床研究中的代表性仍然不足。 审判我们的少数患者来源的异种移植（PDX）开发和试验中心（M-PDTC）提供了一个独特的 帮助解决这些种族/民族差异的机会。该中心的科学前提是， 除了重要的社会经济因素外，健康方面的不平等也给少数种族/族裔造成负担， 美国与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（Baylor College of Medicine）的少数民族癌症患者人数众多， 利用不同种族/少数民族血统的创新PDX模型，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。休斯顿是世界上 这是一个多元化的美国大城市，约20%的居民是非洲裔美国人（AA），约40%是西班牙裔。大学教师 负责两个主要教学医院的临床护理，为大量少数民族人口提供服务：本·陶布 医院（BTH），一家公立医院（91%的病人是少数民族），和迈克尔E。DeBakey VA医疗中心 （MEDVAMC），美国最大的VA医疗中心之一，为东南部的10万多名退伍军人提供服务。 德克萨斯州（约30%为AA）。因此，有非常大的少数癌症患者群体可用于潜在的治疗。 组织捐赠在临床试验中成功招募少数民族患者方面，FDA有着悠久的记录。 除了我们在BTH的大型AA患者人群外，BTH的59%患者为西班牙裔。我们有 组建了一个多学科和多机构的合作团队，汇集了PDX模型的专家 分子生物学和信号通路，动物药物治疗研究，病理学和临床 前列腺癌和乳腺癌的管理从马里兰州和MD安德森癌症中心（MDACC）。我们 理想的定位，以利用我们的机构和我们的种族和民族的大量技术资源， 少数癌症患者，以支持M-PDTC RFA的更广泛目标，特别是 促进这些人群的生物标本捐赠，增加种族和民族多样性， PDXNet储存库在广泛的癌症，以及支持我们的两项研究的具体目标 前列腺癌和乳腺癌的研究项目。很少，如果有的话，癌症中心有这种杰出的 研究基地，大量的非洲裔美国人，西班牙裔和亚洲癌症患者，以及癌症研究所的强大跟踪 成功招募来自我们的集水区（休斯顿）的少数民族患者进入临床试验的记录。此外，委员会认为， 我们的两个研究项目将利用全外显子组测序（WES），全球RNA测序（RNA-seq）， 定量蛋白质组学（qKiP）和代谢组学分析，并将进行有前途的NCI-IND的临床前试验 药物，以发现新的，有效的治疗策略，前列腺癌和乳腺癌的少数群体。