# Polymerase-mediated ultramutagenesis and carcinogenesis in mice

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $552,634

## Abstract

PROJECT SUMMARY/ABSTRACT
 Genetically-engineered mouse models (GEMMs) are essential tools for the study of cancer. However,
there is growing concern that GEMMs fail to recapitulate the mutation burden of human carcinomas. GEMMs
have startlingly low overall mutation rates, far below what is observed in their human counterparts. This makes
such models useful for studies of oncogenic signaling pathways, but greatly restricts their utility for studies of
genetic heterogeneity and clonal variation, tumor immunology, or the impact of mutational load/base
substitution rates on tumor behavior and response to therapy. The latter has become particularly relevant with
the advent of immune checkpoint therapies, given that the best predictor of treatment success is a high
incidence of somatic mutations, irrespective of tumor type. The same limitations are likely to be encountered
with GEMMs based on newer genome-editing methods, pointing to the need for alternative approaches to
optimize with respect to mutational load, which we now know defines so many aspects of tumor biology, clinical
behavior and treatment response.
 In this project, submitted in response to PAR-17-245 “Research Projects to Enhance Applicability of
Mammalian Models for Translational Research”, we propose to generate and characterize the first mouse
cancer models based on polymerase-driven ultramutation. These approaches will 1) catalyze modelling of any
cancer driven by POLE ultramutagenesis and 2) permit efficient “humanization” of any GEMM with respect to
mutational load. Our approach represents a new and widely-applicable route to the creation of mouse models
that recapitulate the mutational loads inherent to human cancer. These new genetic tools and the diverse
animal models they will enable will stimulate a wide range of translational and preclinical investigations for
which GEMMs were previously not well-suited, thus fulfilling the goals of PAR-17-245.

## Key facts

- **NIH application ID:** 9850958
- **Project number:** 5R01CA237405-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** DIEGO H CASTRILLON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $552,634
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850958

## Citation

> US National Institutes of Health, RePORTER application 9850958, Polymerase-mediated ultramutagenesis and carcinogenesis in mice (5R01CA237405-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9850958. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*