R01CA255621

Trial of Statins for Chemoprevention in Hepatocellular Carcinoma - Project Summary

Worldwide, hepatocellular carcinoma (HCC) represents the fifth most common cancer and the second-leading cause of cancer-related mortality. In the U.S., both the HCC incidence and mortality are increasing at an alarming pace. Despite these concerning trends, treatment options for HCC remain limited, and the prognosis is grim, with a 5-year survival rate of just 15%.

Thus, identifying effective strategies to prevent the development of incident HCC represents a critical public health need. A growing body of preclinical and population-based observational data now demonstrate that lipophilic statins, and in particular atorvastatin, reduces hepatic inflammation, cellular proliferation, and cancer cell invasion, and reduces the incidence of HCC, in part by acting on relevant pathways, including the Hippo-YAP signaling pathway.

However, despite these promising data, well-designed randomized controlled trials (RCTs) of atorvastatin for HCC prevention have not yet been reported. Historically, the feasibility of an HCC prevention trial has been limited by large sample size and long lengths of follow-up required to assess target endpoints.

Recently, however, our group has derived and validated a 186-gene expression prognostic liver signature (PLS) that represents an accurate, reproducible, and highly reliable surrogate biomarker for HCC risk in multiple international cohorts of all major viral and non-viral etiologies of cirrhosis. Further, we have demonstrated that therapeutic modulation of the PLS accurately recapitulates future risk of developing incident HCC tumors, both in vivo and in confirmatory human studies. Finally, we and others have demonstrated in human liver tissue samples that atorvastatin modulates the PLS in part by acting on the Hippo-YAP pathway.

Thus, the PLS represents a novel and highly tractable surrogate biomarker endpoint for an RCT of atorvastatin for the reduction of incident HCC risk. In this proposal, we will conduct a phase II RCT in 60 patients with compensated cirrhosis, designed to test the efficacy, safety, and tolerability of 48 weeks of atorvastatin for the reduction of HCC risk, defined by our validated PLS profile.

All subjects will have a high-risk PLS defined at screening liver biopsy, and subjects will be randomly assigned to 1 of 2 study arms for the 48-week study period: atorvastatin 20mg/day or placebo, with appropriate monitoring for the 48-week period, followed by a repeat biopsy at week 48 to assess for improvement in the PLS profile. We will also confirm whether atorvastatin has adequately engaged its targets by evaluating pharmacokinetics/pharmacodynamics, pre/neoplastic markers, and alteration in the Hippo-YAP pathway.

We hypothesize that PLS-based HCC risk level decreases in the atorvastatin arm at the end of 48-week treatment. If atorvastatin treatment is effective, safe, and well-tolerated, it could become the first chemopreventive agent designed to prevent the development of HCC, guided by PLS, in the growing population of patients in the U.S. who are affected by cirrhosis and are at high risk for this devastating complication.

The General Hospital Corporation

TO IDENTIFY CANCER RISKS AND RISK REDUCTION STRATEGIES, TO IDENTIFY FACTORS THAT CAUSE CANCER IN HUMANS, AND TO DISCOVER AND DEVELOP MECHANISMS FOR CANCER PREVENTION AND PREVENTIVE INTERVENTIONS IN HUMANS. RESEARCH PROGRAMS INCLUDE: (1) CHEMICAL, PHYSICAL AND MOLECULAR CARCINOGENESIS, (2) SCREENING, EARLY DETECTION AND RISK ASSESSMENT, INCLUDING BIOMARKER DISCOVERY, DEVELOPMENT AND VALIDATION, (3) EPIDEMIOLOGY, (4) NUTRITION AND BIOACTIVE FOOD COMPONENTS, (5) IMMUNOLOGY AND VACCINES, (6) FIELD STUDIES AND STATISTICS, (7) CANCER CHEMOPREVENTION AND INTERCEPTION, (8) PRE-CLINICAL AND CLINICAL AGENT DEVELOPMENT, (9) ORGAN SITE STUDIES AND CLINICAL TRIALS, (10) HEALTH-RELATED QUALITY OF LIFE AND PATIENT-CENTERED OUTCOMES, AND (11) SUPPORTIVE CARE AND MANAGEMENT OF SYMPTOMS AND TOXICITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO STIMULATE TECHNICAL INNOVATION, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY WOMEN AND SOCIALLY/ECONOMICALLY DISADVANTAGED PERSONS. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING, AND FOSTER PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY WOMEN AND SOCIALLY/ECONOMICALLY DISADVANTAGED PERSONS.

93.393 - Cancer Cause and Prevention Research

National Cancer Institute (NCI) [HHS - NIH]

Boston, Massachusetts 021142621 United States

Single Zip Code

Cancer Prevention and Control Clinical Trials Grant Program (R01 Clinical Trial Required) (PAR-18-559)

Amendment Since initial award the End Date has been extended from 08/31/26 to 08/31/27 and the total obligations have increased 439% from $675,855 to $3,646,155.