UT Southwestern Liver Cancer SPORE - The UT Southwestern (UTSW) Liver Cancer SPORE assembles a multidisciplinary team of basic, clinical, and translational scientists to tackle one of the major health problems in the U.S., liver cancer. The overarching goal of this SPORE is to leverage innovative, groundbreaking basic science discoveries from UTSW investigators to develop personalized medical interventions that can significantly reduce liver cancer mortality. We will particularly focus on hepatocellular carcinoma (HCC), the most common form (>85%) of liver cancer in Texas and the U.S. To accomplish this goal, we take a multi-pronged approach, including prevention of incident HCC and improving efficacy of treatment options for patients with HCC. Given that HCC arises almost exclusively in patients with cirrhosis from viral hepatitis, alcohol abuse, or metabolic dysfunction associated steatotic liver disease (MASLD), HCC prevention in cirrhosis patients is rational and feasible. We will clinically evaluate two complementary approaches of HCC prevention in patients with cirrhosis, and a novel approach to overcome resistance to immune checkpoint blockade to substantially improve HCC mortality. Project 1. Cirrhosis stroma-directed HCC chemoprevention with EGFR inhibition. In this phase II clinical trial, we will test 24-week low-dose epidermal growth factor receptor (EGFR) inhibitor, erlotinib, for safety and efficacy in reducing HCC risk in high-risk patients with cirrhosis. We will explore clinical and molecular variables that affect erlotinib response to guide subsequent phase III clinical trial design. Project 2. Hepatocyte-targeted HCC chemoprevention with Anillin knockdown. Based on our discovery that hepatocyte polyploidy prevents HCC development in cirrhosis, we will perform a phase Ia adjuvant clinical trial in patients with HCC undergoing locoregional therapy to assess an alternative chemoprevention strategy to therapeutically induce polyploidy using a hepatocyte-targeted siRNA for a cytokinesis regulator, Anillin (ANLN-siRNA). We will also develop biomarkers to measure Anillin levels and software to quantify hepatocyte polyploidy to monitor treatment response. Project 3. Targeting telomerase to induce anti-tumor immunity in HCC. Leveraging our basic science discovery that 6-thio-dG shows anti-tumor effect by inducing anti-tumor immunity in telomerase-active cancer, including HCC, we will test the agent in combination with cemiplimab (anti-PD1) as neoadjuvant therapy in a phase Ib clinical trial for patients with early-stage HCC undergoing surgical resection. By analyzing samples from enrolled patients, we will evaluate molecular factors that affect 6-thio-dG response to guide patient selection, improve efficacy, and resolve resistance to 6-thio-dG-based therapy. These Projects are supported by the Administrative and Outreach Core (Core A), Biospecimen and Pathology Core (Core B), and Data Science Core (Core C). The Developmental Research Program (DRP) and Career Enhancement Program (CEP) will contribute to sustainable translational research in liver cancer to impact the disease burden and mortality in Texas and the U.S.
