# Attacking aggressive p53 mutants in gynecologic cancer

> **NIH NIH K22** · UNIVERSITY OF IOWA · 2024 · $186,840

## Abstract

Project Summary/Abstract
I am currently a mentored assistant research scientist in the Department of Obstetrics and Gynecology at the
University of Iowa. My long-term goal is to establish an independent research program to improve outcomes
for women with ovarian and endometrial cancer through the safe delivery of effective and personalized
treatment regimens. I intend to pursue an independent tenure-track faculty position at a competitive research
institution, building upon my postdoctoral training in novel RNA-based therapeutics and current work in
personalized medicine for gynecologic cancers. The objective for my independent K22 research program is to
mechanistically distinguish between common missense p53 mutants and develop synthetic RNA-based
therapeutics to overcome the deleterious functions. Approximately 40-50% of all observed p53 mutations are
single nucleotide variants that result in missense mutations that change a single amino acid. Missense
mutations not only abrogate canonical DNA binding and interaction with co-factors, but also confer new
activities, including transcription of non-canonical targets and new in protein:protein interactions. Studies will
focus on endometrial and ovarian cancer given the widespread occurrence of p53 mutations in these cancer
types and the extremely poor 5-year survival of patients with p53 mutant cancers. I hypothesize that missense
mutations in p53 that result in protein hyperstabilization activate different transcriptomic signatures that can be
perturbed using novel RNA aptamers evolved to be specific for each mutant p53. This work leverages a highly
innovative strategy to isolate native p53 from patient-derived organoid (PDO) cultures, which allows for study
of p53 mutations in their endogenous environment. First, I will determine the mechanism(s) of survival and
chemoresistance for recurrent p53 mutants by calculating the DNA binding specificity native p53 mutants and
link this to genomic localization, gene regulation and chemosensitivity. This work includes a novel approach to
isolate p53 mutant proteins from PDO models to capture the native protein conformation, posttranslational
modifications and splice isoforms. Next, I will restore chemosensitivity in models with p53 mutants by
perturbing the deleterious activity of individual p53 mutants with mutant-specific RNA aptamers. These studies
will provide the first comprehensive assessment of the functional consequences of a large panel of p53
mutants using native protein and establish the feasibility of developing aptamer-based tools that inactivate p53
mutants. This project merges my graduate work in cell signaling, postdoctoral training in RNA aptamer-based
therapeutics and more recent work in translational studies of gynecologic cancers. With funding from this K22
award and my multi-disciplinary collaborators, I will be well-equipped to establish an independent research
program to improve outcomes for women with gynecologic cancer.

## Key facts

- **NIH application ID:** 10894679
- **Project number:** 5K22CA263783-03
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Kristina W Thiel
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $186,840
- **Award type:** 5
- **Project period:** 2022-08-01 → 2025-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10894679

## Citation

> US National Institutes of Health, RePORTER application 10894679, Attacking aggressive p53 mutants in gynecologic cancer (5K22CA263783-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10894679. Licensed CC0.

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