# Mutant p53 gain-of-function as an actionable target in cancer therapy

> **NIH NIH R50** · STATE UNIVERSITY NEW YORK STONY BROOK · 2020 · $212,358

## Abstract

Project Summary
In contrast to other tumor suppressors, 75% of p53 alterations in human cancers are missense mutations in the
DNA-binding domain that generate abnormally stabilized mutant proteins (‘mutp53’). The research program of
Unit Director Dr. Ute Moll’s laboratory generated new mouse models that definitively proved that certain hotspot
missense mutant p53 proteins not only lose their tumor suppressor function, but acquire broad oncogenic gain-
of-function (GOF) activities (‘mutp53GOF’). Our humanized p53R248Q knockin mice (’Q’ mice) provided the
long-sought compelling phenotype of faster onset of all spontaneously arising tumor types and significantly
shorter survival compared to p53null littermates. Importantly, our finding translates to human cancers. In Li-
Fraumeni patients harboring p53 germline mutations, the Q allele dramatically accelerates tumor onset by 10.5
years and leads to increased mortality compared to p53null-like Li-Fraumeni patients. Moreover, TCGA data
suggest that sporadic cancer patients harboring specific GOF alleles have higher death rates than patients with
p53 mutations that are functionally null. GOF contributes to malignant progression with increased proliferation,
invasion, metastasis, chemoresistance, stroma remodeling and reprogrammed metabolism. As central
translational progress, our lab also established that these mice develop strong exploitable dependency on
continued high expression of mutp53 for tumor growth, maintenance and metastasis. We showed that genetic
or pharmacologic (via Hsp90 inhibitors) ablation of mutp53 in autochthonous lymphomas and colorectal cancers
triggers strong cytotoxicity in different hotspot GOF knockin mice, translating to tumor regression, inhibition of
invasion and major gains in survival, even in the absence of wildtype p53. My research builds on these strong
pre-clinical and clinical findings to further explore mutp53GOF and its exploitability in a broader cancer context.
Given the exceptionally high frequency of TP53 mutations across all cancer types, this therapeutic concept is
highly relevant for a wide population of cancer patients. As a research Investigator in the Moll laboratory, I am
actively pursuing two areas of research. 1) I have been leading research on evaluating the therapeutic potential
of mutp53 ablation in other major sporadic carcinomas by testing autochthonous mouse models of liver and
pancreatic cancer. 2) I designed and characterized a new ‘wtp53 to mutp53 switch’ mouse strain and I lead work
identifying the molecular basis of mutp53 GOF-driven tumor formation in vivo using time-resolved ChIPseq/single
cell RNAseq and functional proteome analyses. My ultimate goal is to identify novel therapeutic targets for
mutp53 cancers. In addition to performing bench research to address these biologic and translational questions,
my responsibilities include training of postdocs, graduate and undergraduate students; technology development
for the group and oversight...

## Key facts

- **NIH application ID:** 10042972
- **Project number:** 1R50CA251836-01
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** Alice Nemajerova
- **Activity code:** R50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $212,358
- **Award type:** 1
- **Project period:** 2020-09-11 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10042972

## Citation

> US National Institutes of Health, RePORTER application 10042972, Mutant p53 gain-of-function as an actionable target in cancer therapy (1R50CA251836-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10042972. Licensed CC0.

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