# Functional Analysis of p53 Polymorphic Variants

> **NIH NIH R01** · WISTAR INSTITUTE · 2021 · $391,227

## Abstract

Project Summary
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.

## Key facts

- **NIH application ID:** 10141456
- **Project number:** 2R01CA102184-15A1
- **Recipient organization:** WISTAR INSTITUTE
- **Principal Investigator:** Maureen E. Murphy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $391,227
- **Award type:** 2
- **Project period:** 2005-06-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10141456

## Citation

> US National Institutes of Health, RePORTER application 10141456, Functional Analysis of p53 Polymorphic Variants (2R01CA102184-15A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10141456. Licensed CC0.

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