PROJECT SUMMARY The goals of this Pathway to Independence Career Development proposal are to gain expertise in colorectal cancer (CRC), population science, and experimental therapeutics, with a focus on the development of novel therapeutic strategies for CRC, dependent on the status of the p53 tumor suppressor gene, TP53. The training plan outlined in this proposal will take full advantage of the extensive resources and scientific expertise at The Wistar Institute, and incorporates training with experts at Wistar, Columbia University, and the Fox Chase Cancer Center. My training will be guided by clinical and basic cancer researchers who have successfully mentored predoctoral, postdoctoral, and clinical fellows in academic careers. African Americans have the highest incidence and mortality rates of CRC of any ethnic group in the United States. The most common genetic alterations in CRC include K-Ras, Wnt, and TP53. We have pioneered the analysis of naturally occurring coding region variants of p53 in different populations, with emphasis on the impact of these variants on cancer risk and the efficacy of cancer therapy. With this proposal I take aim at two genetic variants in p53 that exist in African American populations, and their impact on CRC progression and therapy. The P47S variant alters p53 phosphorylation and transcriptional function; this variant is impaired for ferroptotic cell death, and knock-in mice containing the P47S variant are susceptible to a variety of tumor types, including CRC. The Y107H variant shows altered structure of the p53 DNA binding domain, and my data indicate that it too has poorer tumor suppressor function and transcriptional potential. I recently used CRISPR engineering to create a mouse model for the Y107H variant. The P47S and Y107H variants together exist in over half a million African Americans in the United States. The goal of the proposed research is to use these naturally-occurring variants as biologically-relevant tools with which to dissect p53 function. I will explore the following scientific aims: 1) to elucidate the mechanisms whereby the P47S variant promotes colorectal cancer development; and 2) to investigate the role of the African-specific Y107H variant in tumor suppression. The completion of the scientific aims in this proposal will develop my research skills and knowledge in both colorectal cancer and the impact of TP53 variants on cancer risk, as well as gaining a more complete understanding of targeted therapies based upon TP53 genotype. I expect this research to have a profound impact on the understanding, and on the eventual successful elimination, of cancer disparities in African Americans.