# Epigenetically Engineered Mouse Model for Lung Cancer Therapy

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2021 · $365,308

## Abstract

PROJECT SUMMARY (Abstract)
The importance of aberrant DNA methylation in cancer is clear. The fundamental role of DNA methylation in
cancer initiation and progression, however, remains elusive. The use of gene targeting in animal models
definitively demonstrated that genetic mutations at specific genes cause disease. An analogous “epigenetic gene
targeting” approach is urgently needed to advance the field of epigenetics. In human lung cancers, p16 promoter
methylation associated epigenetic silencing is one of the earliest detected epimutations and is thought to function
as a critical initiating event in tumorigenesis. The importance of this epimutation is further underscored by the
associations with distinct gene mutation patterns, cancer prognosis, and response to therapy. However, the
molecular pathways linking aberrant DNA methylation, epigenetic silencing, and tumorigenesis remain poorly
characterized. In this regard, we published the first mouse model demonstrating that targeted p16 epimutation
drives spontaneous tumor development. Importantly, our preliminary studies revealed that p16 epimutation
operates synergistically with oncogenic K-RAS activation to drive lung cancer progression. Based on these
findings, this proposal responds to PAR-20-131: Research Projects to Enhance Applicability of Mammalian
Models for Translational Research. Our overall goals are to establish more faithful murine models of human lung
cancer development and to utilize this epigenetically engineered mouse model for testing novel epigenetic
therapeutic strategies. Specifically, we will: 1 − Employing epigenetic engineering in mice to model advanced
human lung cancers. We propose to establish clinically relevant and immunocompetent mouse models based
on defined genetic and epigenetic alterations to drive benign lung tumor growths towards the ultimate malignant
phenotype. 2 − Testing combinatorial epigenetic therapy in mouse lung tumors carrying a driver p16 epimutation.
We propose to test whether epigenetic targeting drugs and/or anti-PD-L1 immunotherapy can effectively
suppress p16 epimutant lung tumor growth during critical transition points from non-malignant lesions to
adenocarcinoma. These studies will elucidate the functional role of epimutations in lung tumorigenesis in vivo.
Successful completion of the proposed studies will provide a mechanistic rationale to refine ongoing epigenetic
therapy, with the potential to improve survival rates in lung cancer.

## Key facts

- **NIH application ID:** 10272375
- **Project number:** 1R01CA261723-01
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Lanlan Shen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $365,308
- **Award type:** 1
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10272375

## Citation

> US National Institutes of Health, RePORTER application 10272375, Epigenetically Engineered Mouse Model for Lung Cancer Therapy (1R01CA261723-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10272375. Licensed CC0.

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