This revised renewal application requests funding for years 15-19 for a proposal that is devoted to understanding the impact of genetic hypomorphs of the p53 tumor suppressor on cancer risk and therapy. The central premise is that the analysis of cancer-associated genetic hypomorphs of the p53 tumor suppressor can lend critical insight into the key functions of this tumor suppressor in cancer. The proposed research focuses on the African-specific Pro47Ser p53 hypomorph (hereafter S47) that exists in over 800,000 African-descent individuals in the United States and confers increased cancer risk in these individuals. The S47 variant of p53 is defective in the transactivation of a small subset of p53-target genes, particularly those that confer sensitivity to ferroptosis. The overarching hypothesis of the proposed research is that by understanding the biology of P47S and other cancer-associated hypomorphs, two important outcomes are met: the first is the identification of key tumor suppressor functions of p53, which are still not known. The second is that we can use mouse models in order to better understand cancer risk, and uncover superior cancer therapies, for the individuals who possess these variants.
In Aim 1 we will investigate our finding that the tumor micro-environment in S47 mice is more immuno- suppressive, due to increased accumulation of myeloid-derived suppressor cells (MDSCs). MDSCs are potent immunosuppressive cells that directly limit the efficacy of immune checkpoint inhibitors. We will test the efficacy of immune checkpoint inhibitors in WT and S47 mice, and we will test combination therapy in which we target MDSCs.
In Aim 2 we present data that P47S, like two other cancer-associated p53 hypomorphs Y107H and G334R, has impaired ability to transactivate the chromatin modifier PADI4, along with increased propensity to misfold and adopt a mutant p53 conformation. We will investigate the relevance of both activities to tumor suppression by p53.
In Aim 3 we provide PheWAS data indicating that the S47 allele is a highly significant risk factor for bladder cancer in African Americans (p< 6x10-6, OR 7.5). In this aim we investigate the function of S47 in mouse models of bladder cancer, with the goal of better understanding the reasons underlying this significant association. We then follow our published successful protocols to identity novel chemotherapeutic drugs that show improved efficacy in S47 bladder cancer, compared to WT. The combined studies build upon a wealth of published and preliminary data, along with novel mouse models for p53 hypomorphs and the integration of human data throughout. These studies are paramount for our long term goal of understanding the genetic basis of minority cancer disparities, and improving personalized medicine approaches for individuals of African descent.
The proposed research will determine the underlying mechanism(s) for increased cancer risk in individuals with the African-centric p53 hypomorph P47S. This hypomorph exists in over 800,000 African-descent individuals in the United States, and accomplishing these aims has important implications for understanding cancer risk in under-represented populations, and for informing personalized medicine approaches.
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