Projects
The overarching goal of the Liver Cancer SPORE is to leverage innovative, groundbreaking basic science discoveries from UT Southwestern investigators to develop and translate personalized medical interventions that can significantly reduce liver cancer mortality. We 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 if the right chemoprevention agent(s) were available. Therefore, we are clinically evaluating three complementary approaches to significantly reduce HCC mortality.
We are also tackling other areas of need such as early HCC detection, improved diagnostic tools, and alternative treatment strategies through various ongoing pilot projects.
The Liver Cancer SPORE is composed of the following Projects:
Project 1: Cirrhosis stroma-directed HCC chemoprevention with EGFR inhibition
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.
In this phase two clinical trial, we are testing 24-week treatment with low-dose epidermal growth factor receptor (EGFR) inhibitor, erlotinib, for safety and efficacy in reducing HCC risk in high-risk patients with cirrhosis. We are exploring clinical and molecular variables that affect erlotinib response to guide design a subsequent phase three clinical trial.
- Project 1 Specific Aims
1. Evaluate long-term, low-dose erlotinib for efficacy and safety in cirrhosis patients (phase two 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.
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.
Leads
Principal Investigator
Medical Director, Liver Tumor Program and Chief of Hepatology
Project 2: Hepatocyte-targeted HCC chemoprevention with anillin knockdown
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.
In this phase two clinical trial, we are testing 24-week treatment with low-dose epidermal growth factor receptor (EGFR) inhibitor, erlotinib, for safety and efficacy in reducing HCC risk in high-risk patients with cirrhosis. We are exploring clinical and molecular variables that affect erlotinib response to guide design of subsequent phase three clinical trial.
- Project 2 Specific Aims
1. Develop clinical assays to measure ANLN and polyploidy as companion biomarkers for human ANLN inhibition. We will develop a clinical assay to measure human ANLN expression and image analysis software to quantify hepatocyte ploidy in human liver samples for future implementation in a CLIA laboratory.
2. Assess ANLN and ploidy changes in livers after locoregional HCC therapies in humans and mice. To measure the degree of polyploidy change that might be expected in a clinical trial with transient dosing of siANLN, we will perform correlative human studies and functional murine studies. In humans, we will measure how much hepatocyte polyploidy changes after locoregional therapies in pretreatment and explant tissues from liver transplant patients. We will also administer siRNA to mice at the same time as locoregional injuries and assess safety and pharmacodynamic markers.
3. Phase 1a dose escalation adjuvant trial for reducing risk of de novo recurrence in patients with HCC undergoing locoregional therapy. We will conduct an investigator-initiated, phase 1a single dose escalation study using a Bayesian optimal interval design to assess toxicities and to determine the maximum tolerated dose. The primary endpoint is the frequency of adverse events (AEs). Secondary endpoints include the pharmacokinetic and pharmacodynamic effects of siANLN, and exploratory endpoints include recurrence-free survival and changes in cytokinesis/tumor suppressor gene (TSG) expression.
Leads
Principal Investigator
Professor, Children's Medical Center Research Institute at UT Southwestern
Project 3: Targeting telomerase to induce anti-tumor immunity in HCC
Although surgical resection offers a curative option for patients with early-stage HCC, more than 50% experience recurrence within two years. PD-1/PD-L1 inhibitors show efficacy for advanced-stage HCC but have unclear benefit for recurrence-free survival in the adjuvant setting. Neoadjuvant immunotherapy appears more successful than adjuvant therapy in inducing pathological responses and preventing recurrence across multiple tumor types; however, this approach has not been thoroughly evaluated in patients with HCC.
We propose to evaluate a first-in-class anti-cancer agent repurposed at UT Southwestern targeting a novel pathway in TERT-activated HCC. Our study leverages a nucleoside prodrug analog, 6-thio-2’-deoxyguanosine (6-thio-dG), which efficiently and selectively targets telomerase-positive cancer cells, but not non-malignant hepatocytes.
- Project 3 Specific Aims
1. Determine the safety and efficacy of neoadjuvant 6-thio-dG plus immunotherapy in 45 patients with early-stage HCC undergoing surgical resection in a randomized phase 1b clinical trial with two arms: 1) immunotherapy alone, or 2) immunotherapy plus 6-thio-dG. The primary endpoint is safety as measured by treatment-related delay of surgical resection >28 days following last treatment dose. Secondary endpoints are major pathologic response rate, overall response rate, 1-year RFS, overall survival, and adverse events.
2. Assess the mechanism of action and identify predictive biomarkers of 6-thio-dG activity in patient specimens. We will examine telomere induced dysfunctional foci, SLC43A3 expression, and TERT promoter alterations as potential predictive markers of 6-thio-dG activity.
3. Evaluate synergistic anti-tumor immunity of 6-thio-dG plus immunotherapy in patient specimens. Based on the proposed mechanism of 6-thio-dG-mediated anti-tumor immune activation, we hypothesize biomarkers from specific steps will be associated with 6-thio-dG plus PD-1 blockade efficacy: (i) cGAS-STING pathway activity induced by telomere associated DNA damage, (ii) cross-priming of adaptive immunity, and (iii) activation of cytotoxic CD8+ T cells (i.e. transition from immunologically “cold” to “hot” tumor microenvironment).
Leads
