Research

Project Leaders:
Ahmed Kaseb, M.D., CMQ (Clinical)
Michael Curran, Ph.D. (Basic)

There are multiple systemic therapies for the treatment of advanced hepatocellular carcinoma (HCC), but overall survival improvement is modest and response rates are low. Resection and liver transplantation are curative treatments; however, only about 20% of HCC patients are eligible, and early recurrence is frequent. Because the predominant molecular alterations in HCC are not druggable, targeting immune checkpoints, such as programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), may be a promising alternative strategy. The anti-PD1 drug, nivolumab, was recently approved for HCC therapy. With a 20% response rate, anti-PD1 therapy is encouraging. While increased immune response by targeting PD-1 and CTLA-4 pathways has been reported in unresectable HCC, immunotherapy strategies have not yet been evaluated in neoadjuvant (pre-surgery) and adjuvant (post-surgery) settings. In a randomized perioperative trial with nivolumab ± ipilimumab (anti-CTLA-4) for resectable HCC, we observed complete pathologic responses that correlated with increased CD8+ T cell infiltration and CD8/Treg ratio. We also showed that c-MET inhibitors upregulate PD-L1 expression in HCC cells, which may allow HCC cells to escape from T cell killing. We further showed that combination of c-MET inhibitors and anti-PD-1 synergistically suppresses HCC development in mice.

Our long-term translational goal is to modulate immune cells in the HCC microenvironment to improve outcome in patients with advanced HCC or resectable HCC. We hypothesize that neoadjuvant immune checkpoint therapy can trigger an immune response that may lead to delay in recurrence or increased resectability, and that immune infiltration or fibrosis stage can affect treatment response. We also hypothesize that simultaneously targeting immune checkpoint signaling and checkpoint molecule expression can improve immunotherapy efficacy. We propose a neoadjuvant/adjuvant clinical trial targeting PD-1 ± CTLA4 in surgical HCC patients to delay recurrence and in locally advanced unresectable HCC patients to increase resectability. We will evaluate novel combination therapies including anti-PD-1 and agents upregulating PD-L1 expression, such as c-MET inhibitors, in HCC. The impact of project 1 would be increased access to surgery for a larger number of HCC patients and improvement in overall survival.

Project Leaders:
David Tweardy, M.D. (Basic)
Jean-Nicolas Vauthey, M.D. (Clinical)
Ahmed Kaseb, M.D., CMQ (Clinical)

While surgical resection is potentially curative for early stage HCC, care of advanced stage disease is limited to treatment with sorafenib, regorafenib or nivolumab, which increase survival by three to four months. In patients who undergo resection, five-year recurrence is ~70%.

Our long-term translational goal is to improve outcomes in patients with advanced stage HCC and in post-operative HCC patients. Activation of signal transducer and activator of transcription (STAT) 3 occurs in ~60% of HCCs. In collaboration with Tvardi Therapeutics, Inc., we identified TTI-101 (C188-9), a potent, non-toxic and orally bioavailable inhibitor of STAT3. Administration of TTI-101 to mice that develop liver steatosis and fibrosis followed by HCC led to arrest of tumor growth and a marked reduction in liver injury and fibrosis. An MD Anderson Phase I study of patients with solid tumors, including HCC, showed no toxicity through dose level (DL)3 and partial clinical response after two cycles at DL2. We developed a clinical laboratory improvement amendments (CLIA)-certified immunohistochemistry (IHC) assay and score for pY-STAT3 in HCC tumors. We hypothesize that STAT3 contributes to HCC tumor growth and immune resistance, as well as HCC development in the setting of liver inflammation and fibrosis. We hypothesize further that use of a STAT3 inhibitor, such as TTI-101, will be more effective at treating advanced HCC when combined with standard therapy (nivolumab) than nivolumab alone and will prevent postoperative recurrence. We will determine: 1) the safety and early effectiveness of TTI-101 when used in combination with nivolumab in patients with non-resectable HCC, 2) the utility of pY-STAT3 score of HCC patient tumors or adjacent non-tumoral liver in predicting postoperative recurrence, 3) if TTI-101 adjuvant therapy reduces HCC recurrence. The impact of this project would be increased survival of patients with advanced stage HCC and reduced recurrence of HCC in patients who undergo surgical resection.

Project Leaders:
Laura Beretta, Ph.D. (Basic)
Ernest Hawk, M.D., M.P.H. (Applied)
Andrew Futreal, Ph.D. (Basic)

HCC incidence rates are increasing in the United States, in part due to the epidemics of obesity and diabetes. The greatest increase is seen in South Texas Hispanics. Our studies in the Cameron County Hispanic Cohort (CCHC) established from a community with high rates of obesity and diabetes, showed that chronic liver disease is also common. Non-alcoholic fatty liver disease (NAFLD), a common liver manifestation of obesity and diabetes, ranges from simple steatosis to non-alcoholic steatohepatitis (NASH). Advanced fibrosis is the main risk factor for HCC in NAFLD patients. We reported a 3.5% prevalence of advanced fibrosis in CCHC, with a population attributable fraction of 65% for central obesity. We implemented liver fibrosis screening in CCHC, using vibration-controlled transient elastography (VCTE), and reported a 14% prevalence of clinically significant fibrosis. Prevalence of significant liver fibrosis reached 28% in obese and diabetic subjects. Strong associations between gut microbiota changes and progression of NAFLD to NASH and HCC have been reported. Bile acids are important mediators in gut-liver cross-talk. Furthermore, we identified fatty acids as non-invasive markers of NAFLD activity and liver fibrosis in NAFLD patients.

Our long-term translational goal is to determine the contributing factors and molecular drivers of liver fibrosis in obese and diabetic Hispanics in South Texas, and identify those at risk of progression to advanced fibrosis and HCC, so preventive interventions can be implemented. We will enroll 900 obese and diabetic subjects who will be screened for liver fibrosis. Bile acids, fatty acids and gut microbiome features will be measured. Study participants will be followed prospectively and liver fibrosis will be again assessed at 36 months. We will determine the risk factors associated with liver fibrosis in this population. We will identify molecular markers associated with liver fibrosis stages and develop a model predicting fast liver fibrosis progression. The impact of this project would be reduction of HCC mortality rates through early intervention and prevention.

Directors:
Asif Rashid, M.D., Ph.D.
Manal M. Hassan, M.D., M.P.H., Ph.D.
Yun Shin Chun, M.D., FACS

The Biobank and Pathology Core (Core 1) facilitates innovative translational research in prevention, detection and treatment of hepatocellular carcinoma (HCC), by providing clinically and histologically well-characterized tissue and blood specimens from patients with HCC. Core 1 serves as the comprehensive resource for the SPORE projects providing centralized collection, storage and distribution of biospecimens, gathering of histopathological/molecular profiles and clinicopathological information of patients with HCC who are referred to MD Anderson. Reflecting the rising incidence of HCC, the number of HCC patients who sought and received care at MD Anderson has increased every year, from 277 patients in 2013 to 580 patients in 2017, a two-fold increase. Core 1 will maintain a tissue and blood repository, provide pathological review, create and maintain a database with modules for: sample identification, characterization, processing, quality control, research tissue requests, sample transactions and tracking. Finally, Core 1 will fill future needs that may include: a) TMAs, b) Immuno-profiling of surgically-resected tumors and adjacent liver, and c) Development of novel, clinically-relevant CLIA-compliant tests.

Directors:
Peng Wei, Ph.D.
Yisheng Li, Ph.D.

The primary goal of MD Anderson Cancer Center SPORE in HCC is to facilitate innovative translational research through the elucidation of underlying molecular mechanisms, characterizing novel biomarkers and functional pathways and exploiting novel targets for treatment. The Biostatistics and Bioinformatics Core serves multiple needs for the planning and conduct of the SPORE's research. Core 2 is a comprehensive, multi-lateral resource for designing clinical and basic science experiments, performing statistical analyses, developing innovative statistical methodology and publishing the research results generated from this HCC SPORE. Core 2 provides guidance in design and conduct of clinical trials and other experiments arising from SPORE projects and developmental and career enhancement projects. Core 2 will also provide biostatistical and bioinformatic modeling, simulation techniques and data analyses needed by the projects and other cores to achieve their specific aims. Core 2 will generate statistical reports for all projects, assist project investigators in publishing scientific results and develop innovative statistical and bioinformatics methods pertinent to translational HCC studies, including new unsupervised approaches to biomarker signature construction.

Directors:
Laura Beretta, Ph.D.
Ahmed Kaseb, M.D., CMQ

The responsibilities of the Administrative Core include monitoring and planning of scientific activities, providing scientific direction for the SPORE and ensuring an interdisciplinary translational research emphasis and integration within MD Anderson and NCI Translational Research Programs.