# Molecular Mechanisms by which Statins Prevent and Reverse Hepatocellular Carcinoma

> **NIH NIH U01** · STANFORD UNIVERSITY · 2023 · $341,920

## Abstract

Project Summary/Abstract
 Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. HMG-CoA
reductase (HMGCR) inhibitors, statins, show high potential in the prevention and treatment of cancer including
HCC. We will investigate the mechanism by which statins fight against HCC and discovering the biomarkers to
predict the therapeutic effects. Through our previously published work, we have used our conditional transgenic
mouse models of HCC to identify a novel pathway that statins suppress MYC signaling to execute the anti-cancer
properties. Also, we identified that MYC rewires metabolic pathways to promote fatty acid synthesis in addition
to glucose and glutamine pathways. Inhibition of fatty acid synthesis by TOFA elicits dramatic regression of MYC
driven tumors and the efficacy correlates to MYC level. Statin (e.g., Atorvastatin) blocks MYC phosphorylation in
our MYC-driven HCC model and inhibit tumor initiation and progression (see our Preliminary Results). We
hypothesize that the MYC pathway is suppressed by statins and this is a mechanism by which statins can prevent
and treat HCC, both through direct anti-oncogene effects as well as by restoring immune surveillance. We will
determine the mechanisms by which statins protect against HCC, we propose to 1) evaluate the anti-cancer
efficacy of statins at different progression stages of MYC driven HCC (before MYC induction, early stage of
tumorigenesis, late stage of HCC) and the condition of association with NASH; 2) identify specific metabolism
pathways regulated by statin in MYC-HCC; 3) define the changes of immune system and specific
effectors/cytokines influenced by statin; 4) discover the biomarkers that can predict the therapeutic effect of statin
in prevention of HCC. Our team includes expertise in Medical Oncology, the MYC oncogene and Tumor
Immunology (Felsher), Gastroenterology and HCC (Dhanasekaran) and Hepatology and liver disease (Verna
and Brown). Dr. Verna and Dr. Brown are members of the Liver Cirrhosis Network (LCN) clinical program (RAF-
CA-23-023) and are currently investigating the effect of lipid lowing medications (Statins) in patients with
compensated NASH, ALD, cholestatic and cryptogenic cirrhosis. The LCN study provides us with a unique
opportunity to identify mechanisms through use of our preclinical transgenic mouse model of HCC that can be
evaluated using human clinical samples to available to us through the LCN. Our work will help identify lead to
the identification of the mechanisms by which statins can block HCC as well as identify biomarkers that can
predict when these agents are most likely to be useful in preventing HCC.

## Key facts

- **NIH application ID:** 10856787
- **Project number:** 1U01CA288433-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** DEAN W FELSHER
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $341,920
- **Award type:** 1
- **Project period:** 2023-09-19 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10856787

## Citation

> US National Institutes of Health, RePORTER application 10856787, Molecular Mechanisms by which Statins Prevent and Reverse Hepatocellular Carcinoma (1U01CA288433-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10856787. Licensed CC0.

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