University of Texas Southwestern Liver Cancer SPORE

Participant Sites

University of Texas Southwestern Medical Center

Principal Investigators

Overview

The UT Southwestern (UTSW) Liver Cancer Specialized Program of Research Excellence (SPORE) brings together a multidisciplinary team of basic, translational, and clinical scientists to address liver cancer. Liver cancer is a major health issue in the U.S. The program’s overarching goal is to transform innovative scientific discoveries from UTSW into personalized medical interventions that reduce liver cancer mortality, with a specific focus on hepatocellular carcinoma (HCC), which accounts for over 85% of liver cancer cases in the U.S.

Our multi-pronged strategy targets both prevention of HCC and improvement of treatment efficacy. HCC primarily develops in patients with cirrhosis from causes such as viral hepatitis, alcohol misuse, or metabolic dysfunction-associated steatotic liver disease (MASLD). This makes preventive strategies in this population both rational and feasible. We will clinically evaluate two complementary approaches to HCC prevention and one to improve immunotherapy response.

Project 1 evaluates a stroma-directed chemoprevention strategy using low-dose erlotinib, an EGFR inhibitor, in high-risk patients with cirrhosis. This phase II trial assesses its safety and efficacy, and identifies clinical and molecular predictors of response.

Project 2 focuses on hepatocyte-targeted chemoprevention via Anillin knockdown. Building on our discovery that hepatocyte polyploidy reduces HCC risk, this phase Ia trial uses a targeted siRNA (ANLN-siRNA) to induce polyploidy in patients receiving locoregional therapy. Biomarker and software development will support monitoring of Anillin levels and polyploidy.

Project 3 targets resistance to immunotherapy by combining 6-thio-dG. This combination activates anti-tumor immunity in patients with telomerase-positive cancers who have received immunotherapy as neoadjuvant treatment for early-stage HCC. A phase Ib trial will assess efficacy and resistance mechanisms through analysis of patient samples.

These projects are supported by three cores: Administrative and Outreach (Core A), Biospecimen and Pathology (Core B), and Data Science (Core C). The Developmental Research Program (DRP) and Career Enhancement Program (CEP) sustain future translational research and contribute to reducing liver cancer mortality in Texas and nationwide.

Project 1: Cirrhosis-stroma-directed hepatocellular carcinoma (HCC) chemoprevention with EGFR inhibition

Project 1 Co-Leaders:

Yujin Hoshida, MD PhD (Basic Co-leader)
Amit Singal, MD MS (Clinical Co-leader)

Specific Aims

HCC has a poor prognosis due to the limited efficacy of existing therapies. 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 surrogate biomarker, prognostic liver secretome signature (PLSec), which were validated in multiple prospective cohorts. PLS/PLSec are therapeutically modifiable, and therefore used as surrogate endpoints in HCC chemoprevention trials.

We 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, reduces HCC nodules in rodent models of cirrhosis-driven HCC. In our phase I trial of 7-day erlotinib treatment, phospho-EGFR staining was reduced at a dose of 25 mg/day and PLS-based HCC risk level was reduced at 50 mg/day (1/3 of approved chemotherapeutic dose) without notable adverse events.  Based on these findings, we are testing our hypothesis that low-dose erlotinib treatment is an effective and safe strategy of HCC chemoprevention.

Aim 1. Evaluate long-term low-dose erlotinib for efficacy and safety in patients with cirrhosis (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 high-risk PLSec. We will assess PLSec modulation (primary endpoint), safety profile, and change in quality of life (secondary endpoints), as well as 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 patients with cirrhosis. We will evaluate pre-treatment PLSec, clinico-histological variables, and EGF SNP associated with HCC risk, as well as on-treatment modulation of PLSec/PLS and HCC risk-associated immunohistochemical markers for association with the primary endpoint.

This project establishes 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.

Project 2: Hepatocyte-targeted HCC chemoprevention with Anillin knockdown

Project Co-Leaders:

Hao Zhu, MD (Basic Co-leader)
David Hsieh, MD (Clinical Co-leader)

Specific Aims

Locoregional therapies are frequently used to treat HCC. However, recurrence is common, partly due to a “field defect” from cirrhosis resulting in frequent de novo tumors. Therefore, tertiary prevention would be an ideal approach to reduce HCC-related mortality. Incomplete cytokinesis is a normal physiologic mechanism that drives polyploidization of hepatocytes. We discovered that knockdown of a cytoskeletal scaffolding protein called anillin (ANLN) can suppress hepatocyte cytokinesis, induce polyploidization, and protect the liver from malignant transformation. In partnership with Alnylam, we performed siRNA studies of long-term ANLN knockdown, resulting in prolonged cytokinesis inhibition and HCC protection in mouse models, but did not disrupt liver function.

We seek to evaluate ANLN mRNA siRNAs to prevent recurrence of de novo tumors in cirrhotic HCC patients after locoregional therapies.

Aim 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.

Aim 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 pre-treatment 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.

Aim 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.

Project 3: Targeting telomerase to induce anti-tumor immunity in HCC

Project Co-Leaders:

Daolin Tang, MD, PhD (Basic Co-leader)
Adam Yopp, MD (Clinical Co-Leader)

Specific Aims

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 that targets 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. Our preliminary data indicate that 6-thio-dG not only induces cell cycle arrest and apoptosis in telomerase-reactivated HCC cells but also activates the innate/adaptive immunity (i.e., cGAS-STING pathway and CD8+ T cells). Therefore, we hypothesize 6-thio-dG will enhance efficacy of immune checkpoint inhibitor–based therapies. Partnering with MAIA Biotechnology, we propose the following aims:

Aim 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.

Aim 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.

Aim 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 that biomarkers from specific steps are 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).

Administrative Core

Core Co-Directors:

Amit Singal, MD, MS
Yujin Hoshida, MD, PhD

Specific Aims

The Administrative and Outreach Core (Core A) will provide essential administrative services and support for the UTSW Liver Cancer SPORE. Core A Specific Aims will achieve the objective of organizing a complex network of interactions involving numerous investigators, staff, cores, and advocates. A specific management plan is in place for rigorously evaluating metrics of existing projects, terminating underperforming projects, advancing developmental/pilot projects into major projects, and supporting career development of junior investigators. The Specific Aims of Core A are:  

Aim 1. Oversee and direct all scientific and administrative aspects of the SPORE, including research/data management, fiscal oversight and adherence, and communication.

Aim 2. Oversee and coordinate with the Developmental Research Program (DRP) and Career Enhancement Program (CEP) to provide fiscal, organizational, and outreach support.

Aim 3. Coordinate and oversee activities of the Patient Advocacy Panel. 

Aim 4. Oversee and facilitate resolution of scientific disputes.

Biospecimen and Pathology Core

Core Co-Directors:

Purva Gopal, MD
Adam Yopp, MD

Specific Aims

Our Core B infrastructure ensures processes are in place to support each of the main SPORE projects, DRP, and CEP. The overarching goal of Core B is to expand and provide the infrastructure and services necessary for the successful completion of all SPORE projects and to promote internal and external collaborations to UTSW through the following Specific Aims:  

Aim 1. Preserve and expand a liver cancer and cirrhosis specimen biorepository and infrastructure with clinical and molecular genomics annotation and integration within a web portal for distribution to SPORE investigators and collaborators.

Aim 2. Develop, expand, and utilize innovative tissue and cell resources (including tissue microarrays, tumor cell lines, and immortalized liver cell lines) that will aid successful completion of SPORE projects. 

Aim 3. Provide pathology services and expertise in histo-morphologic analysis of human- and animal-derived specimens to SPORE investigators and collaborators.

Data Science Core

Core Director:

Chul Ahn, PhD
Yang Xie, PhD

Specific Aims

Core C is organized into three groups: Biostatistics, Bioinformatics, and Data Management. Each group implements innovative data analytic approaches and provides day-to-day support for all SPORE investigators. Each project has a dedicated biostatistician and a bioinformatician as the direct point of contact for all data science needs. Core personnel ensure the appropriate statistical design, linkage, validation, and interpretation of results for statistical and biological significance, ensuring reproducibility and rigor in reporting research findings. Core C members will assist SPORE investigators with study design, biostatistical/bioinformatic data analysis, data management, and monitoring the proper conduct. Core C provides resources for external researchers to gain appropriate access to SPORE-related datasets to validate and further analyses. While initially using well-established methods, Core members contribute innovative approaches to catalyze discovery and translation as needed. Core C will provide dedicated data science support for SPORE investigators via the following Specific Aims:  

Aim 1. Provide biostatistical support for experimental design with power calculation, statistical analysis, and interpretation for all Liver Cancer SPORE-related research activities.  

Aim 2. Provide bioinformatics support for genomic and imaging data preprocessing, analysis, interpretation, and visualization for all Liver Cancer SPORE-related research activities.  

Aim 3. Maintain and expand a web-based database and analysis tools by our liver cancer biorepository for streamlined and integrated access to liver cancer biospecimens and clinical/molecular data for SPORE investigators and the broader liver cancer research community.

Overall, the IT infrastructure for the Liver Cancer SPORE ensures secure storage and access to data, streamlined sharing of data, state-of-the-art analysis capabilities, and rigorous scientific interpretation to promote translational research in liver cancer and reduce liver cancer mortality in the U.S.

Developmental Research Program (DRP)

Program Co-Directors:

Yujin Hoshida, MD, PhD
Daolin Tang, MD, PhD

Specific Aims

The DRP will provide seed funding for promising translational projects that can significantly impact liver cancer research and care. The DRP will fund pilot and/or high-risk/high-impact projects using innovative approaches with the potential to generate groundbreaking discoveries that will significantly improve liver cancer prevention, early detection, or treatment efficacy. 

Aim 1. Serve as a mechanism to provide seed funding for promising projects. The DRP award will provide seed funding for selected projects via the SPORE DRP budget, UTSW institutional commitments, and other outside funding sources when available.  

Aim 2. Identify and recruit promising scientists and physician-scientists. The DRP award will aid in the recruitment of researchers from all fields whose work reflects emerging trends and innovations that could impact the liver cancer field and encourage these investigators to apply their expertise toward cross-disciplinary liver cancer translational research. 

Aim 3. Facilitate the development and progress of the DRP projects and the transition of successful projects into competitive applications for peer-reviewed funding. The DRP leadership assists awardees with (1) identification of other funding resources, and (2) preparation of successful applications. 

Aim 4. Support SPORE DRP awardees to ensure that scientific advances are translated into improved outcomes for liver cancer patients.

Career Enhancement Program (CEP)

Program Co-Directors:

Elisabeth Martinez, PhD 
Hao Zhu, MD
Suzanne Conzen, MD

Specific Aims

The CEP coordinates career development opportunities and provides seed funding to (1) foster careers of early-stage scientists and clinicians interested in translational liver cancer research; and (2) facilitates more established investigators refocusing their research program. The CEP will fund projects using innovative approaches, with potential to generate groundbreaking discoveries that improve liver cancer research.

Aim 1. Identify, recruit, and mentor promising early-career scientists and physician-scientists. CEP awards serve to recruit researchers from all fields whose work reflects trends and innovations that could impact the field and mentors these investigators to apply their expertise toward liver cancer translational research. 

Aim 2. Serve as a mechanism to provide funding for promising career-enhancing projects via the SPORE CEP budget, UTSW institutional commitments, and other outside funding sources. 

Aim 3. Facilitate development and progress of CEP investigators and transition of their projects into competitive applications for peer-reviewed funding. The CEP serves as a springboard to accelerate investigators’ progress toward independent funding and/or promotion to full SPORE projects. 

Aim 4. Support CEP awardees to ensure scientific advances are translated into improved outcomes for liver cancer patients. The CEP fosters collaboration with the SPORE and external investigators, facilitates their research, and provides resources from SPORE cores.

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