# Refolding Mutant p53: A Strategy for Cancer Prevention in Li-Fraumeni Syndrome

> **NIH NIH U54** · RESEARCH INST OF FOX CHASE CAN CTR · 2024 · $391,886

## Abstract

PROJECT SUMMARY - PROJECT 1
 Li-Fraumeni syndrome (LFS), an inherited disorder arising in heterozygous carriers of germline mutations
in TP53, is associated with early-onset cancers in many different tissues of origin. Because TP53 has been
studied so extensively, a unique opportunity exists to intervene early – prior to tumor formation – in LFS
individuals.
 Whether germline or somatic, most cancer-associated TP53 mutations are missense mutations that
disrupt p53’s ability to bind DNA. While some of these mutations map to residues in direct contact with DNA,
many do not. Rather, these mutations reduce p53’s thermodynamic stability, so that an insufficient amount of
(mutant) p53 is correctly folded: this leads to loss of function (LOF). Many of these mutations also confer
oncogenic gain of function (GOF) activities. Among Li-Fraumeni individuals, evidence suggests that the earliest
stages in the emergence of precancerous lesions, and progression of these lesions to cancer, derive from mutant
p53’s GOF activities.
 Ongoing work in the Karanicolas lab focuses on developing drugs that bind and stabilize the folded
conformation of mutant p53, to directly correct the missense defects that underlie the LOF and GOF activities.
These “refolder drugs” are designed to bind a region on the protein surface that is separate from all of p53’s
most common mutations, so that the same drug can be applied irrespective of the specific mutation. We have
tested these drugs in diverse cancer cell lines harboring many different mutations in TP53. Through these
studies, we have confirmed that these refolder drugs both: 1) restore LOF from mutant p53, and 2) revert mutant
p53’s GOF activities.
 The objectives of our proposed project are three-fold. First, we will define the set of mutations
characteristic of LFS individuals that can be addressed by this new class of agents. Second, we will optimize our
current “best” agent to enhance its expected safety and efficacy in animal studies. Third, we will test the safety
of the resulting agents’ in mice heterozygous for a TP53 mutation seen frequently in LFS individuals, and efficacy
in a mouse model of p53-mediated squamous carcinoma that provides clear milestones of the progression from
precancer to cancer. Successful completion of these studies will serve as important proof-of-concept that these
p53 refolding agents hold the potential to become new drugs for prevention and early interception of cancer in
LFS individuals.

## Key facts

- **NIH application ID:** 10909964
- **Project number:** 5U54CA272686-03
- **Recipient organization:** RESEARCH INST OF FOX CHASE CAN CTR
- **Principal Investigator:** John Karanicolas
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $391,886
- **Award type:** 5
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10909964

## Citation

> US National Institutes of Health, RePORTER application 10909964, Refolding Mutant p53: A Strategy for Cancer Prevention in Li-Fraumeni Syndrome (5U54CA272686-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10909964. Licensed CC0.

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