The University of Texas MD Anderson Cancer Center SPORE in Hepatocellular Carcinoma
The University of Texas MD Anderson Cancer Center
Principal Investigator(s):
Laura Beretta, PhD
Ahmed Kaseb, MD, CMQ
- Principal Investigator(s) Contact Information
- Overview
- Project 1: Targeting the PD-1 Pathway in HCC
- Project 2: Targeting STAT3 with an Oral Small Molecule to Treat HCC
- Project 3: Non-Invasive Assessment of Liver Fibrosis Stage and Progression in Obesity and Diabetes; a Hispanic Population Study
- Administrative Core
- Biobank and Pathology Core
- Statistics and Bioinformatics Core
- Developmental Research Program
- Career Enhancement Program
Principal Investigator(s) Contact Information
Laura Beretta, PhD
Professor
The University of Texas MD Anderson Cancer Center
1515 Holcombe Blvd., Unit 1051
Houston TX, 77030
(713) 792-9100
Ahmed Omar Kaseb, MD, CMQ
Professor
The University of Texas MD Anderson Cancer Center
1515 Holcombe Blvd., Unit 426
Houston, TX 77030
(713) 792-2828
Overview
The overall goal of the University of Texas MD Anderson Cancer Center SPORE in Hepatocellular Carcinoma (HCC) is to improve outcomes for HCC patients and reduce the mortality rates of HCC through early intervention. HCC is the 2nd leading cause of cancer death worldwide and the incidence of new HCC cases is projected to rise to 1,341,344 cases by 2035. In the United States (U.S.), deaths from HCC is increasing at the highest rate of all cancer sites. The highest incidence of HCC observed in the States is on the Mexico-US Border. Hispanics in South Texas have the highest rates of HCC in the U.S (37.5 diagnosed cases per 100,000). Reflecting the rising incidence trends, the number of HCC patients seeking care at MD Anderson Cancer Center has doubled over the last 5 years. The relative 5-year survival rate for HCC is 16%. This poor prognosis is due to multiple factors: 1) the majority of HCC cases are diagnosed at an advanced stage, not amenable to curative surgical treatment; 2) resected cases have high rates of recurrence; 3) HCC often occurs in the context of advanced chronic liver disease, cirrhosis in particular, limiting treatment options; 4) the first FDA-approved first line systemic therapy was sorafenib, offering a 2.8 months improvement in overall survival and a response rate of 2%; and 5) the recently approved front- and second- line therapies include other tyrosine kinase inhibitors and immunotherapy drugs, but again improvement in overall survival and response rates are very low.
Our SPORE includes three translational research projects:
- Project 1. Targeting the PD-1 pathway in HCC
- Project 2. Targeting STAT3 with an oral small molecule to treat HCC
- Project 3. Non-Invasive assessment of liver fibrosis stage and progression in obesity and diabetes; A Hispanic population study
These projects are supported by three Cores: Core 1: The Pathology and Biobanking Core; Core 2: The Biostatistics and Bioinformatics Core; and the Administration Core. This SPORE also includes a Career Enhancement Program to support HCC research from junior investigators and a Developmental Research Program to support innovative translational research in HCC.
Project 1: Targeting the PD-1 Pathway in HCC
Project Co-Leaders:
Ahmed Kaseb, MD, CMQ (Clinical)
Michael Curran, PhD (Basic)
There are multiple systemic therapies for the treatment of advanced HCC; however, overall survival improvement is modest and response rates are low. Resection and liver transplantation are curative treatments; however, ~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 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 which 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 improve overall survival.
Project 2: Targeting STAT3 with an Oral Small Molecule to Treat HCC
Project Co-Leaders:
David Tweardy, MD (Basic)
Jean-Nicolas Vauthey, MD (Clinical)
Ahmed Kaseb, MD, 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 3-4 months. In patients who undergo resection, 5 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 3: Non-Invasive Assessment of Liver Fibrosis Stage and Progression in Obesity and Diabetes; a Hispanic Population Study
Project Co-Leaders:
Laura Beretta, PhD (Basic)
Ernest Hawk, MD, MPH (Applied)
Andrew Futreal, PhD (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.
Administrative Core
Core Directors:
Laura Beretta, PhD
Ahmed Kaseb, MD, CMQ
The responsibilities of the Administrative Core include monitoring and planning of scientific activities, providing scientific direction for the SPORE, ensuring an interdisciplinary translational research emphasis and integration within MD Anderson and NCI Translational Research Programs.
Biobank and Pathology Core
Core Directors:
Asif Rashid, MD, PhD
Manal M. Hassan, PhD
The Biobank and Pathology Core (Core 1) is to facilitate innovative translational research in prevention, detection and treatment of HCC, by providing clinically and histologically well-characterized tissue and blood specimens from patients with HCC. Core 1 will serve as the comprehensive resource for the SPORE projects providing centralized collection, storage and distribution of biospecimens; and gathering of histopathological/molecular profiles, and clinicopathological information of patients with hepatocellular carcinoma (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 2-fold increase during the most recent 5 years. 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 which may include: a) TMAs, b) Immuno-profiling of surgically-resected tumors and adjacent liver, and c) Development of novel, clinically-relevant CLIA-compliant tests.
Statistics and Bioinformatics Core
Core Directors:
Peng Wei, PhD
Yisheng Li, PhD
The primary goal of the University of Texas 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 will serve multiple needs for the planning and conduct of the SPORE's research. Core 2 will be 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 will provide 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, will assist project investigators to publish scientific results and will develop innovative statistical and bioinformatics methods pertinent to translational HCC studies including new unsupervised approaches to biomarker signature construction.
Developmental Research Program
Program Directors:
James C Yao, MD
Randy L Johnson, PhD
The purpose of the Developmental Research Program (DRP) is to fund promising projects by investigators whose current work may not focus exclusively on HCC, but who propose highly innovative translational studies of HCC that could become full SPORE projects or compete successfully for funding outside of the SPORE. The DRP provides a unique venue for making available significant financial support, and for demonstrating active institutional support, through a program that is rapidly responsive to new ideas or initiatives. Moreover, this program is rooted in a spirit of collaboration espoused by the SPORE investigators, who have an extensive track-record of bringing investigators from other disciplines into HCC research. The strength of the Developmental Research Program rests in its ability to make available financial support needed to access all the critical expertise and resources within the entire SPORE. This will allow us to develop collaborative, multi-investigator, multi-institutional research projects with the support of innovative, investigator-initiated projects that have the potential to flourish into reliable and productive translational research projects that make a path from basic and/or population research projects into research focused on human clinical specimens/patient populations.
Career Enhancement Program
Program Directors:
James C Yao, MD
Randy L Johnson, PhD
The Career Enhancement Program (CEP) is to use the resources at the MD Anderson Cancer Center to train exceptional young investigators in the early detection, prevention, and treatment of HCC, with the hope that their research will reduce the mortality from this disease. The intent of each CEP award is to prepare the selected scientists to become international leaders in academic research relevant to HCC. The most promising young investigators will be identified, mentored through an individualized clinical and laboratory development plan, trained in grant and manuscript writing and in developing leadership skills. Awardees will be required to attend all SPORE meetings and one national meeting where they can interact with liver cancer scholars and HCC SPORE leaders. Awardees will also be required to present their research at the annual SPORE conference and, if possible, to submit the results of their project for publication. Past awardees will be invited to all SPORE events and encouraged to apply for funding in the area of research developed under the CEP and to keep seeking advice from the SPORE leaders to further develop their careers.