# Therapeutic modulation of a proteomic HCC risk signature with statins in patients with liver cirrhosis

> **NIH NIH U01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $323,446

## Abstract

Hepatocellular carcinoma (HCC) is a major cirrhosis complication producing an alarming rise in mortality. The
prognosis for HCC is poor due to extremely high recurrence rate even after curative-intent surgical therapies and
limited efficacy of available medical therapies. Given its refractory nature, prevention of HCC in cirrhosis patients
will be the most impactful strategy to improve its poor prognosis; however, effective HCC prevention remains a
major unmet need. Retrospective and pre-clinical studies have suggested that statins are a viable form of HCC
chemoprevention, with a differential effect between lipophilic and hydrophilic statins. Further evidence suggests
that statins may modulate HCC risk through Hedgehog and Hippo signaling pathways. However, the clinical
validation of statins has been hampered by the requirement for large and lengthy clinical trials to define their
clinical utility. To overcome these challenges, we have developed a serum-based HCC risk biomarker, the
Prognostic Liver Secretome signature (PLSec). Of note, PLSec is therapeutically modifiable and the magnitude
of PLSec modulation is associated with future HCC incidence as demonstrated by our previous and preliminary
studies. In a retrospective case-control series, PLSec-based HCC risk level was lower in cirrhosis patients on
statins compared to non-users. Based on these observations, PLSec is now being tested as a surrogate endpoint
in HCC chemoprevention trials of atorvastatin (TORCH trial). To achieve the goal of establishing statins as viable
HCC chemoprevention with PLSec as a surrogate endpoint, we have assembled a team of cirrhosis and HCC
experts to analyze serum samples from three nation-wide multi-center prospective cohorts (Liver Cirrhosis
Network, Southern Liver Health Study, and Mass General Brigham cohorts) and two randomized controlled trials
(TORCH and LCN RESCU trials). Aim 1. Validate lower biomarker-based HCC risk level in cirrhosis patients on
statins compared to non-users. We will validate our preliminary finding in prospective case-control series of
cirrhosis patients form the three cohorts. We will explore patient characteristics and types of statins associated
with the PLSec-based HCC risk level, along with mechanistic markers of Hedgehog/Hippo signaling. Aim 2.
Determine magnitude of biomarker-based HCC risk modulation after starting or stopping statins. We will conduct
target trial emulation mimicking single-arm clinical trials with statins to determine the magnitude of PLSec
modulation in patients who start or stop statins from three cohorts. We will explore patient characteristics and
types of statins associated with PLSec-based HCC risk modulation, along with mechanistic markers. Aim 3.
Compare biomarker-based HCC risk modulation between lipophilic and hydrophilic statins. We will compare the
magnitude of placebo-adjusted PLSec modulation between lipophilic (atorvastatin) and hydrophilic (rosuvastatin)
statins by analyzing serum samples fr...

## Key facts

- **NIH application ID:** 10934594
- **Project number:** 5U01CA288375-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** RAYMOND T CHUNG
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $323,446
- **Award type:** 5
- **Project period:** 2023-09-25 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10934594

## Citation

> US National Institutes of Health, RePORTER application 10934594, Therapeutic modulation of a proteomic HCC risk signature with statins in patients with liver cirrhosis (5U01CA288375-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10934594. Licensed CC0.

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