# Implications of Driver Mutations for Progression of Hepatocellular Carcinoma

> **NIH NIH R21** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $243,090

## Abstract

PROJECT SUMMARY: Hepatocellular carcinoma (HCC), or primary liver cancer, is the 5th most common cancer
globally and the 2nd most common cause of cancer death worldwide. HCC is often diagnosed at a late stage at
which 85% of patients are not candidates for curative surgical operations; moreover, HCC is notoriously resistant
to chemotherapy and other systemic treatments, resulting in a 5-year survival rate of 17.2%. Since cancer is
driven by the accumulation of genetic driver mutations conferring selective growth advantages, potential exists
for utilization of precise gene-editing techniques to investigate the impact of driver mutations on
chemotherapeutic susceptibility for chemoresistant cancers including HCC. This proposal employs the
innovative Oncopig Cancer Model (OCM)—a transgenic pig model that recapitulates human cancer through
induced expression of heterozygous KRASG12D and TP53R167H driver mutations—to test the hypothesis that
compelling phenotypic differences in malignant potential and chemoresistance are induced by accumulation of
distinct driver mutations. In this proposal, OCM HCC with distinct driver mutational profiles will be created through
CRISPR-Cas9 directed knockout of ARID1A and/or AXIN1—observed in 10-15% of human HCC—on existing
KRASG12D and TP53R167H transgene germline mutated OCM cells for investigation of the effects on HCC
chemoresistance and malignant potential. AXIN1 mutations result in WNT signaling activation, while ARID1A
plays a key role in chromosome remodeling, promoting HCC development, migration, and proliferation. This
approach will allow in vitro and in vivo investigation of the contribution of driver mutational profiles on malignant
potential and treatment susceptibility in a clinically relevant large animal model with similar anatomy, physiology,
metabolism, immunity, and genetics compared to humans. Through assessment of the effects of sequential,
spatially controlled driver mutation accumulation on clinically relevant tumor phenotypes, this proposal addresses
PQ4: Can we develop tools to directly change the expression or function of multiple chosen genes simultaneously
and use these tools to study the range of changes important for human cancer? Our rationale is that the creation
and validation of in vivo systems to model HCC will provide a foundation for translational and transformative
study of the contribution of driver mutational profiles on clinically relevant phenotypes, ultimately advancing the
development of novel, targeted HCC therapeutic approaches. We plan to test our central hypothesis by pursuing
the following Specific Aims: (1) To perform simultaneous and stepwise CRISPR-Cas9 directed ARIDA1A and
AXIN1 mutation in already established KRASG12D and TP53R167H mutated OCM HCC cell lines, and to define in
vitro malignant potential and chemoresistance; (2) To define the in vivo effects of distinct HCC driver mutational
profiles on malignancy in a clinically relevant OCM cirrhotic liver microenv...

## Key facts

- **NIH application ID:** 9989800
- **Project number:** 5R21CA219461-02
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Ron C Gaba
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $243,090
- **Award type:** 5
- **Project period:** 2019-08-07 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989800

## Citation

> US National Institutes of Health, RePORTER application 9989800, Implications of Driver Mutations for Progression of Hepatocellular Carcinoma (5R21CA219461-02). Retrieved via AI Analytics 2026-06-03 from https://api.ai-analytics.org/grant/nih/9989800. Licensed CC0.

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