# Targeting tumor metabolism and immune environment via beta-catenin: Towards precision medicine in HCC

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $620,173

## Abstract

Chronic liver disease and its common sequela cirrhosis, are growing public health concerns, and major risk
factors for the development of hepatocellular cancer (HCC). HCC incidence and mortality is growing in the
USA. Optimal medical therapies for HCC are lacking. FDA approved agents are modestly effective. Immune
checkpoint inhibitors (ICIs) including PD-1 inhibitors Nivolumab and Pembrozilumab, have been both
approved and show good response rates but only in a subset of HCC cases. Biomarkers of response remain
unknown. Recent years have seen a revolution in HCC GWAS studies to identify molecular drivers. Mutations
in CTNNB1 activate b-catenin in the Wnt pathway & seen in up to 37% of HCCs. However, b-catenin activation
alone does not lead to HCC. Analysis of 2 large HCC cohorts (TCGA & French) revealed CTNNB1 mutations to
co-occur with alterations in MET, MYC, TERT, NFE2L2, MLL2, ARID2 & APOB. Overexpression/activation of
Met along with CTNNB1 mutations is seen in ~11% of HCCs. Coexpression of these genes in a subset of
hepatocytes using sleeping beauty transposon/transposase (SB) & hydrodynamic tail vein injection (HTVI) led
to HCC by 6 weeks in mice (hMet-b-catenin model). Gene expression analysis confirmed 70% similarity
between hMet-b-catenin model and HCC patient subset with Met activation & CTNNB1 mutations. In aim 1,
we will generate and characterize mouse models using SB/Crispr and HTVI to co-express mutant CTNNB1 and
other genes frequently co-altered in subsets of human HCC including MYC, TERT, NFE2L2, MLL2, ARID2, &
APOB. We already show HCC development in Met-b-catenin, MYC-b-catenin, TERT-b-catenin & NFE2L2-b-
catenin, while others are ongoing. Comparison of gene expression between mouse models and human HCC
subsets will validate the relevance of these models justifying a more comprehensive cellular & molecular
characterization for innovative therapies. We will also test dependence of all mutant CTNNB1-mouse models to
b-catenin by using of lipid nanoparticles (LNP) containing CTNNB1-siRNA (CTNNB1-LNP) to suppress b-
catenin and assess response as we have shown for Kras-b-catenin (akin to hMet-b-catenin) model. In aim 2, we
will focus on b-catenin-glutamine synthetase (GS)-glutamine-mTORC1 axis in mutant-CTNNB1 HCC, recently
discovered and reported by us (Publication in Cell Metabolism). All mutant-CTNNB1 driven HCC models with
all co-occurrences will be tested for response to mTORC1 inhibitors like Everolimus and RM-006 (novel
exclusive mTORC1 inhibitor) and to upstream GS via genetic deletion of GS in established HCCs or via use of
irreversible GS inhibitor L-methionine sulfoximine (MSO) and glutaminase inhibitor CB-839 that hampers
production of glutamate, a substrate for GS to generate glutamine. In aim 3, we will investigate how to make b-
catenin-active HCCs shown by us to be resistant to ICIs (publication in Cancer Discovery), sensitive to ICIs
through use of combination therapy. Using an immunogenic Myc-lucOS-mutant-b-catenin...

## Key facts

- **NIH application ID:** 10224895
- **Project number:** 5R01CA251155-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Amaia Lujambio
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $620,173
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10224895

## Citation

> US National Institutes of Health, RePORTER application 10224895, Targeting tumor metabolism and immune environment via beta-catenin: Towards precision medicine in HCC (5R01CA251155-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10224895. Licensed CC0.

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