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Last Updated: 09/30/19

The University of Texas MD Anderson Cancer Center SPORE in Hepatocellular Carcinoma

The University of Texas MD Anderson Cancer Center

Principal Investigators:

Laura Beretta, PhD
Laura Beretta, PhD
Ahmed Omar Kaseb, MD, CMQ
Ahmed Omar Kaseb, MD, CMQ

PRINCIPAL INVESTIGATORS CONTACT INFORMATION

Laura Beretta, PhD
Professor
Department of Molecular and Cellular Oncology
MD Anderson Cancer Center
1515 Holcombe Blvd, Unit 1051
Houston TX, 77030
Phone: (713) 792-9100
Fax: (713) 794-3270
Email: lberetta@mdanderson.org

Ahmed Omar Kaseb, MD, CMQ
Professor
Department of Gastrointestinal Medical Oncology
Editor-in-Chief, Journal of Hepatocellular Carcinoma
MD Anderson Cancer Center
1515 Holcombe Blvd., Unit 426,
Houston, TX 77030
Phone: (713) 792-2828
Fax: (713) 563-0541
E-mail: akaseb@mdanderson.org

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 with 854,000 new cases diagnosed globally and 810,000 deaths in 2015. The incidence of new HCC cases globally is projected to rise to 1,341,344 cases by 2035. In the United States (U.S.), while death rates declined for all cancers combined and for most cancer sites in the past 10 years, deaths from HCC increased at the highest rate of all cancer sites, and HCC incidence rates increased sharply, second only to thyroid cancer. The burden of HCC is not equally distributed throughout the U.S., the highest incidence being observed in States on the Mexico-US Border. Texas ranks second in incidence of HCC, with a 5-year rate of 11.4 cases per 100,000 compared to the nation rate of 7.6. Within Texas, Hispanics in counties bordering Mexico have the highest rates of HCC in the U.S., with 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 increased every year, from 277 patients in 2013 to 580 patients in 2017, a 2-fold increase over the most recent 5 years. The relative 5-year survival rate for HCC is 16%. The poor prognosis of HCC is due to multiple factors: 1) the vast majority of HCC cases are diagnosed at an advanced stage, not amenable to curative surgical treatment (resection or liver transplantation); 2) even resected cases suffer from high rates of recurrence (up to 50% in 2 years and 70% in 5 years); 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 which offers a 2.8 months improvement in overall survival and a dismal 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.

In this SPORE application, 3 projects together with 3 cores will: 1) evaluate the effect of checkpoint therapy in neoadjuvant and adjuvant HCC settings and determine optimal combinations with checkpoint therapeutics to enhance the anti-tumor immune response; 2) determine the prognostic significance of phosphorylated STAT3 as a biomarker for postoperative recurrence and evaluate TTI-101 (C188-9), a STAT3 inhibitor developed in-house, as a post-operative adjuvant; 3) evaluate the combination of nivolumab and TTI-101 in the treatment of patients with advanced stage HCC; 4) perform extensive screening for liver fibrosis in obese and diabetic Hispanics in South Texas, and identify non-invasive biomarkers of fibrosis stage and progression in this underserved population highly affected by non-alcoholic steatohepatitis and HCC.

PROJECT 1: TARGETING THE PD-1 PATHWAY IN HCC

Project Leaders:
Ahmed Kaseb, MD, CMQ (Clinical)
Michael Curran , PhD (Basic)

There are multiple systemic therapies currently approved for the treatment of advanced HCC; however, the overall survival improvement is modest and the overall response rates are universally low. Resection and liver transplantation are curative treatments for HCC; however, less than 20% of HCC patients are eligible for resection and early recurrence is frequent (50% in 2 years). 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, opening opportunities for more effective therapeutic approaches. In resected HCC samples, we found tumor-infiltrating T cells expressing PD-1 and CTLA-4, surrounded by a dense macrophage infiltrate rich in the checkpoint ligands PD-L1 and PD-L2. 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 pilot randomized perioperative trial with nivolumab ± ipilimumab (anti-CTLA-4) for resectable HCC, we observed complete pathologic responses in 2 cases that correlated with an increase in CD8+ T cell infiltration and CD8/Treg ratio. Based on the 6 patients accrued to date, none had drug related events that led to delaying or canceling surgery and we didn’t encounter grade 3 or 4 adverse events. The tyrosine kinase c-MET is overexpressed in HCC, and multiple c-MET inhibitors have been developed and evaluated in clinical trials in HCC. However, the reported outcomes were disappointing. We 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 the 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 in HCC 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 the efficacy of HCC immunotherapy can be improved by simultaneously targeting immune checkpoint signaling and checkpoint molecule expression. 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 this project would be increased access to surgery for a larger number of HCC patients and improve overall survival in patients with advanced HCC.

ROJECT 2: TARGETING STAT3 WITH AN ORAL SMALL MOLECULE TO TREAT HCC

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

While surgical resection is potentially curative for early stage hepatocellular carcinoma (HCC), care of advanced stage disease is limited to treatment with sorafenib, regorafenib, or nivolumab which increase survival by 3-4 months. Even in patients who undergo resection, recurrence within 5 years occurs in ~70%. Therefore, there is an urgent need for new therapeutic strategies to treat advanced disease and to prevent postoperative recurrence.

Our long-term translational goal is to improve outcomes in patients with advanced stage HCC and in post-operative HCC patients. More than 90% of HCC cases arise in the setting of hepatic injury and inflammation, which involve production of several cytokines, notably hepatocyte growth factor (HGF) and interleukin-6 (IL-6) that activate signal transducer and activator of transcription (STAT) 3. STAT3 is a master regulator of most of the key hallmarks and enablers of cancer and its activation occurs in approximately 60% of HCCs where it is a predictor of tumor recurrence and contributes to immune resistance in HCC by regulating the development, recruitment, and the immunosuppressive activity of myeloid-derived suppressor cells (MDSCs). Our group, in collaboration with a clinical-stage pharmaceutical firm (Tvardi Therapeutics, Inc.), used computer-based docking and lead-compound optimization strategies to identify 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 (hepatocyte-specific Pten knockout mice) led to arrest of tumor growth, as well as marked reduction in liver injury and fibrosis. A Phase I study of patients with solid tumors, including HCC, at MD Anderson showed no toxicity through dose level (DL) 3 and resulted in a partial clinical response after two cycles at DL2 in the first HCC patient entered into the trial. Tvardi collaborated with the Department of Pathology at MD Anderson to develop a clinical laboratory improvement amendments (CLIA)-certified IHC test and score for pY-STAT3 levels by immunohistochemistry (IHC), which was further developed into a pY-STAT3 score for 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 the safety and early effectiveness of TTI-101 when used in combination with nivolumab in patients with surgically non-resectable HCC. We will determine the utility of the pY-STAT3 score of HCC patient tumors or adjacent non-tumoral liver in predicting postoperative recurrence. We will determine 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 Leaders:
Laura Beretta, PhD (Basic)
Ernest Hawk, MD, MPH (Applied)
Andrew Futreal, PhD (Basic)

HCC incidence and mortality rates are rapidly increasing in the United States, in part due to the epidemics of obesity and diabetes. The greatest increase has been seen in Hispanics in South Texas. Our studies in the Cameron County Hispanic Cohort (CCHC) established from a community with high rates of obesity (52%) and diabetes (28%), showed that chronic liver disease is also common (42%). Non-alcoholic fatty liver disease (NAFLD), the most 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 first reported a 3.5% prevalence of advanced fibrosis in CCHC, with a remarkable population attributable fraction of 65% for central obesity. We then implemented liver fibrosis screening in CCHC, using vibration-controlled transient elastography (VCTE), and reported a 14% prevalence of clinically significant fibrosis (stage ≥F2). The 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 and bile acids are important mediators in this gut-liver cross-talk. Furthermore, we identified fatty acids as non-invasive markers of NAFLD activitiy and liver fibrosis in patients with NAFLD.

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, the community in the United States with the highest rate of HCC, and identify those at risk of progression to advanced fibrosis and therefore HCC, so preventive interventions can be implemented. We hypothesize that demographic, clinical, and molecular (microbiome features, bile acids, fatty acids) parameters are associated with liver fibrosis stages in obese Hispanics with diabetes. We hypothesize further that a model based on these parameters will predict fast fibrosis progression and thus increased risk for HCC development in these subjects. We will enroll 900 obese and diabetic CCHC subjects and 500 obese and diabetic Hispanic patients scheduled for liver biopsy at participating liver clinics. All study participants will be screened for liver fibrosis with VCTE and plasma bile acids, plasma fatty acids and gut microbiome features will be measured. Study participants identified with fibrosis ≥F2 will be followed prospectively and liver fibrosis will be again assessed by VCTE and/or liver biopsy at 36 months. We will determine the performance of VCTE against liver fibrosis for fibrosis staging in the study population. We will also determine the prevalence and risk factors associated with liver fibrosis in obese and diabetic Hispanics in South Texas. We will identify the molecular markers among those measured that are associated with liver fibrosis stages. We will identify a model incorporating selected parameters from Aim 1 and molecular markers from Aim 2 in predicting fast liver fibrosis progression in obese Hispanics with diabetes. 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.

CORE 1: BIOBANK AND PATHOLOGY CORE

Core Directors:
Asif Rashid, MD, PhD
Manal M. Hassan, PhD
Yun Shin Chun, MD

The primary objective of 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 with an overall goal of centralizing the 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 of HCC. The specimens included in this repository are: a) Fresh frozen tumor and adjacent liver tissues from surgically resected HCCs or from biopsy samples; b) Paraffin-embedded tumor and adjacent liver tissue from surgically-resected HCCs or from biopsy specimens; c) Blood samples (serum, plasma, buffy coat) from HCC patients; d) Core needle biopsy and fine needle aspirate specimens. Currently, 2618 tissue specimens from 219 HCC patients and blood specimens from 1824 HCC patients are available in the Liver Tumor Bank. During the duration of the HCC SPORE grant, Core 1 will continue to collect tissue and blood specimens, with the following anticipated numbers: resected tissue (200 patients), biopsies (75 patients) and blood samples (1000 patients). Core 1 will provide pathological review for all clinical specimens utilized in the SPORE projects and will provide histopathological services as necessary. In addition, Core 1 will create and maintain a database for all HCC specimens collected, using a customized database with modules for comprehensive sample identification, characterization, processing, sample/slide quality control, research tissue requests, sample transactions, and tracking of tissue samples. Finally, Core 1 will anticipate future needs and fill niches for which no reagents currently exist. These include: a) TMAs, b) Immuno-profiling of surgically-resected tumors and adjacent liver, and c) Development of novel, clinically-relevant CLIA-compliant tests.

CORE 2: BIOSTATISTICS 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 Hepatocellular Carcinoma (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. This is a collaborative effort that will accomplish these aims by integrating laboratory and translational research. The Biostatistics and Bioinformatics Core will serve multiple needs for the planning and conduct of the SPORE's research. Based on a strong track record for providing biostatistical and computational support for translational 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 the design and conduct of clinical trials and other experiments arising from the ongoing research of the SPORE, including SPORE projects, Developmental and Career Enhancement projects, and other cores. 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

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 hepatocellular carcinoma, but who propose highly innovative translational studies of hepatocellular carcinoma 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 hepatocellular carcinoma 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

Directors:
James C Yao, MD
Randy L Johnson, PhD

The central goal of 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 hepatocellular carcinoma (HCC), with the hope that their research will reduce the mortality from this disease. To achieve this goal, the CEP will provide two annual awards of $50,000 each, to two individuals for a two years period, funded from the SPORE and matching funds from MD Anderson. Over the five years of the grant, we expect to mentor up to six investigators. 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.