# Altered mRNA splicing dependent on mutant p53 identifies novel therapeutic vulnerability in pancreatic cancer

> **NIH NIH R00** · YALE UNIVERSITY · 2022 · $245,749

## Abstract

PROJECT SUMMARY AND ABSTRACT
CANDIDATE: I am a postdoctoral research fellow co-mentored by Drs. Steve Leach and Omar Abdel-Wahab at Memorial
Sloan Kettering Cancer Center (MSKCC). I have research training background in population and molecular epidemiology,
cancer predisposition, cancer biomarker discovery and validation, and molecular and cellular approaches to dissect
signaling pathways in disease. My current research focuses on the role of mutant p53 and aberrant alternative splicing in
pancreatic ductal adenocarcinoma (PDAC). My goal as an applicant of the K99 award is to pursue answers to the
research questions where we hope to identify therapeutic opportunities for pancreatic cancer patients. My long-term goal
is to become an independent investigator with the focus of uncovering the transcriptomic foundations of highly aggressive
PDAC tumors dictated by well-known driver and unexplored mutations and expression of alternatively spliced variants. To
reach this goal, my objectives are to broaden my familiarity and expertise with experimental approaches necessary for the
experimental plan outlined in the research strategy, develop further autonomy in research, and recruit and train talented
students.
RESEARCH: Recent studies have identified PDAC patient molecular subtypes based on gene expression profiles, where
the subtype with the worst survival outcome displays enrichment of 1) mutations in TP53, and 2) altered expression of
genes encoding the RNA processing machinery. The overarching goal of this proposal is to determine how mutated p53
regulates and depends on specific patterns of alternative mRNA splicing for promotion, initiation, and maintenance of
PDAC. My preliminary data shows that the most commonly mutated form of oncoprotein p53, R175H, preferentially
promotes splicing of poly-C sequences cassette exon mRNAs, while repressing the inclusion of exons with poly-purine
sequences. The poly-C sequences result in the expression of proline-rich, SH3 binding domains in protein isoforms of a
class of regulators of small-GTPases, including Ras and Rho. These observations led to my hypothesis that p53R175H
alters RNA splicing of GTPase regulators that drive transformation of KRAS-mutant PanIN, to promote PDAC
pathogenesis, and presents a potential mechanism of cellular transformation. In addition, we have found that small-
molecule inhibitors of the core RNA splicing factors significantly reduced tumor growth and extended the survival of PDAC
mice expressing p53R172H, whereas no effect was seen in the absence p53R172H. This suggests that p53R175H’s dependence
on regulating gene expression through control of AS may be a viable opportunity to therapeutically intervene and discover
vulnerabilities for other p53 mutations in PDAC.
ENVIRONMENT: MSKCC is an ideal place for me to perform the research outlined in this proposal and obtain the
necessary training and knowledge to become an independent faculty member at a major university. First, I am bei...

## Key facts

- **NIH application ID:** 10399536
- **Project number:** 5R00CA226342-05
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Luisa Escobar Hoyos
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $245,749
- **Award type:** 5
- **Project period:** 2020-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10399536

## Citation

> US National Institutes of Health, RePORTER application 10399536, Altered mRNA splicing dependent on mutant p53 identifies novel therapeutic vulnerability in pancreatic cancer (5R00CA226342-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10399536. Licensed CC0.

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