Project 1: Cirrhosis-stroma-directed HCC chemoprevention with EGFR inhibition

Ut Southwestern Medical Center, Dallas TX

Investigators

Abstract

Hepatocellular carcinoma (HCC) is the leading cause of death in patients with cirrhosis. HCC prognosis is poor due to limited efficacy of existing therapies. Thus, HCC chemoprevention in patients with cirrhosis is likely a high-impact strategy to improve survival, although it remains an unmet need. We previously defined hepatic transcriptome-based Prognostic Liver Signature (PLS) and its serum protein-based surrogate biomarker, Prognostic Liver Secretome signature (PLSec), which were successfully validated in phase 3 biomarker studies in multiple prospective cohorts of patients with cirrhosis. Of note, PLS/PLSec are therapeutically modifiable, and therefore used as surrogate endpoints in our ongoing HCC chemoprevention trials. Our pre-clinical studies identified activation of epidermal growth factor receptor (EGFR) signaling in hepatic myofibroblasts as a chemoprevention target encoded in the PLS/PLSec that generates a cancer-permissive tissue microenvironment. An EGFR inhibitor, erlotinib, significantly reduces HCC nodules in rodent models of cirrhosis-driven HCC, greater than observed for other potential chemoprevention agents. In our recent phase I trial of 7-day erlotinib treatment in cirrhosis, phospho-EGFR staining was reduced at 25 mg/day and PLS-based HCC risk level was reduced at 50 mg/day (1/3 of approved chemotherapeutic dose) with no notable adverse event. Based on these findings, we will test our hypothesis that long-term, low-dose erlotinib treatment is an effective and safe strategy of HCC chemoprevention in patients with cirrhosis. Aim 1. Evaluate long-term low-dose erlotinib for efficacy and safety in cirrhosis patients (phase II randomized placebo-controlled clinical trial): We will evaluate 24-week low-dose erlotinib (50 mg/day) or placebo in 60 patients with cirrhosis (1:1 randomization) with a high-risk PLSec. We will assess PLSec modulation (primary endpoint), safety profile and change in quality of life (secondary endpoints), and changes in tissue-based PLS and immunohistochemical markers of EGFR signaling, cell proliferation, neoplastic change, and myofibroblast activation and incident HCC development. Aim 2. Identify factors associated with response to long-term low-dose erlotinib in cirrhosis patients. We will evaluate pre-treatment PLSec, clinico-histological variables, and EGF SNP associated with HCC risk, and on-treatment modulation of PLSec/PLS and HCC risk-associated immunohistochemical markers for association with the primary endpoint. We will also conduct spatial molecular profiling to explore strategies to improve erlotinib response. This EPPS project will establish a new cirrhosis stroma-directed HCC chemoprevention for a subsequent pivotal phase III trial toward its clinical translation. We will also identify clinical/molecular factors associated with erlotinib response to guide patient selection and design of future phase III trial. We will further gain insight about spatial heterogeneity in the therapeutic response in human cirrhotic tissue. Collectively, this proposed study will contribute to a transformative improvement of HCC mortality by enabling individual risk-guided, molecular targeted, safe, and affordable chemoprevention of this deadly cancer.