Thursday, November 21, 2024
11/21/2024
This application is prepared in response to the FOA: Administrative Supplements to Support Cancer Disparity Collaborative Research (PAR-22-114) to support our UO1 grant (2UO1 CA199288-06, active till 06/2026) in the NIH/NCI Pediatric Preclinical In Vivo Testing Program (PIVOT). Our objective is to characterize the racial/ethnic nature of a panel of 165 patient-derived orthotopic xenograft (orthotopic PDX or PDOX) models of pediatric brain tumors, to determine disparities in therapeutic responses among racial/ethnic groups, and to understand genetic and epigenetic variations that contribute to such disparities. Our long-term goal is to include well-defined animal model system of diverse racial/ethnic groups to advance cancer disparity research in pediatric brain tumors. Brain tumor is the number one cause of cancer related death in children. Similar to many adult cancers, health disparities have been identified. In addition to socioeconomic and socio-environmental factors, differences of tumor biology may also play a role, as adult cancers have shown distinct gene expression, DNA methylation and mutation profiles among racial/ethnic groups. Our hypothesis that the racial/ethnic-specific genetic components contribute to cancer disparity of pediatric brain tumors and affect their responses to therapy. We hypothesize that the inclusion of minority patient-derived PDOX models will further support the evaluation and prioritization of racial/ethnic appropriate anti-cancer drugs. To test these hypotheses, we propose three Specific Aims. Aim 1: Perform genetic ancestry analysis of our PDOX models to define their racial/ethnic origin. We will supplement self-reported racial/ethnic information with genetic ancestry analysis with EthSEQ analysis of RNAseq data and Infinium Global Screening Array (GCD) analysis to our existing PDOX models (including the 101 models with self-reported racial/ethnic information) to achieve a complete and genetic-based determination/inferrence of race/ethnicity of our model system. Aim 2: Determine the landscape of active drugs against group 3 medulloblastoma in Black, Hispanic and White Children. We have 62 models of medulloblastoma, including 43 models with self-reported race/ethnicity. Since group 3 is the most aggressive subtype, we will a) complete a high throughput drug screening (8,000 drugs) in 10 models from Black, 10 from Hispanic and 10 from White children, respectively; b) understand racial/ethnic-specific mechanisms of action by correlating active drugs with the underlying genetic and epigenetic abnormalities. Aim 3. Integrate minority derived PDOX models in future preclinical drug testing in NIH/NCI PIVOT program. We will add racial/ethnic information as a new criteria of model selection to include minority derived PDOX models as often as possible. Completion of this study will provide a large panel of animal models representing a diverse range of racial/ethnic groups that can be widely distributed to facilitate biological studies of cancer disparity; and generate a catalog of active anticancer drugs for Black, Hispanic and White children with group 3 medulloblastoma, which in turn These findings will impact clinical trials by promoting the inclusion of race/ethnicity as an eligibility criterion.
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