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

项目总结

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.