Mayo Clinic Hepatobiliary SPORE
Mayo Clinic
Principal Investigator(s):
Mark McNiven, PhD
Lewis Roberts, MB, ChB, PhD
- Principal Investigator(s) Contact Information
- Overview
- Project 1: Fibrolamellar Hepatocellular Carcinoma
- Project 2: Therapeutic Inhibition of Fibroblast Growth Factor and YAP Signaling in Cholangiocarcinoma: Preclinical Studies and Clinical Trial
- Project 3: Inhibition of SCD1 as a therapeutic strategy for HCC
- Project 4: Viroimmunotherapy
- Administrative Core
- Biostatistics and Bioinformatics Core
- Biospecimen and Pathology Core
- Developmental Research Program
- Career Enhancement Program
- Institutional SPORE Website
Principal Investigator(s) Contact Information
Mark McNiven, PhD
Professor of Biochemistry and Molecular Biology
Mayo Clinic
200 First Street SW
Rochester, MN 55905
(507) 284-0683
Lewis Roberts, MB, ChB, PhD
Professor of Medicine
Mayo Clinic
200 First Street SW
Rochester, MN 55905
(507) 266-3239
Overview
The Mayo Clinic Hepatobiliary SPORE is focused on combating the high lethality of hepatobiliary cancers, one of the fastest increasing cancer types, in four exceptional and diverse translational research projects:
Project 1: Fibrolamellar Hepatocellular Carcinoma
Project 2: Therapeutic Inhibition of Fibroblast Growth Factor and YAP Signaling in Cholangiocarcinoma: Preclinical Studies and Clinical Trial
Project 3: Inhibition of SCD1 as a therapeutic strategy for HCC
Project 4: Immunovirotherapy
This cutting-edge research environment is designed to develop much needed diagnostic tests, biomarkers, and therapies for three distinct cancers of the liver and biliary system: hepatocellular carcinoma, cholangiocarcinoma, and fibrolamellar hepatocellular carcinoma.
The Mayo Clinic SPORE in Hepatobiliary Cancer is supported by three cores to provide administrative, tissue, and data services to SPORE investigators. Additionally, the SPORE supports several innovative translational research projects through the Developmental Research Program and Career Enhancement Program, which supports junior faculty members.
Project 1: Fibrolamellar Hepatocellular Carcinoma
Project Co-Leaders:
Sanford M. Simon, PhD (Basic Co-Leader)
Michael S. Torbenson, MD (Clinical Co-Leader)
Fibrolamellar hepatocellular carcinoma (FLHCC) is often a lethal disease affecting primarily children and young adults. The disease presents with vague symptoms, and as a result, it is usually diagnosed at an advanced stage. Thus, even for those who undergo surgical resection, there remains a high rate of recurrence. There is a lack of both existing diagnostic tests and systemic therapies, hence diagnosis with the disease has an overall poor prognosis. Comparative analysis of the whole genome of FLHCC tissue to adjacent normal tissue revealed no consistent differences, with one critical exception. We found 15 out of 15 tumor samples had a single deletion of approximately 400 kB in chromosome 19, a deletion that results in a chimera between the heat-shock protein, DNAJB1, and the catalytic subunit of protein kinase A, PRKACA.1 This work has now been reproduced at many institutions and the same deletion confirmed in every patient (n>280)2 in the absence of any other recurrent alterations in the DNA.3 These striking genetic findings demonstrate a clear link to the chimera in the pathogenesis of FLHCC. In light of this recent discovery, we aim to develop the first diagnostics and curative therapeutics to block the driver of the tumor (chimera), with the intent to improve patient care. The FLHCC chimera offers an enticing therapeutic target: it is in all FLHCC tumors, there are no other known consistent changes, and there has been therapeutic success with other cancers driven by chimeric kinases.
Project 2: Therapeutic Inhibition of Fibroblast Growth Factor and YAP Signaling in Cholangiocarcinoma: Preclinical Studies and Clinical Trial
Project Co-Leaders:
Gregory J. Gores, MD (Basic Co-Leader)
Mitesh J. Borad, MD (Clinical Co-Leader)
Cholangiocarcinoma (CCA) is a devastating disease with limited surgical and medical therapies. Further improvements in therapeutic outcomes will depend upon a better understanding of the molecular pathogenesis of this cancer. To this end, following the description of fibroblast growth factor receptor 2 (FGFR2) fusions in a subset of patients with intrahepatic CCA,1 we have recently described a novel, autocrine, signaling pathway linking FGFR2 and Hippo signaling pathways in human CCA cell lines. This oncogenic signaling pathway requires ligand and is independent of FGFR2 gene fusions. Specifically, FGFR2 signaling results in activation of the Hippo-effector protein, Yes-associated protein (YAP), a co-activator of transcription. YAP upregulation led to subsequent FGFR upregulation, and targeting of the FGF pathway with the panFGFR inhibitor BGJ398 was therapeutic in animal models of CCA.2 In extending these observations, we have generated preliminary data implicating Src family kinases (SFKs) as a potential mechanism of signal transduction from the FGF receptors to YAP oncogenic signaling. Based on these preliminary data we have formulated the CENTRAL HYPOTHESIS that CCA progression can be driven by FGFR2-mediated YAP tyrosine phosphorylation (pTyr) by SFKs. Three questions generated by this hypothesis are: (i) How does FGFR2 signaling lead to YAP nuclear translocation (activation) and subsequent FGFR expression? (ii) Can a specific threshold be defined for the percentage/intensity of YAP nuclear staining that would serve as a biomarker for response to FGFR- directed therapy? and (iii) Is targeted FGFR inhibition effective in patients without receptor fusions but who have activation of YAP?
Project 3: Inhibition of SCD1 as a therapeutic strategy for HCC
Project Co-Leaders:
Steven R. Alberts, MD (clinical science lead)
Tushar C. Patel, MB, ChB (clinical science lead)
John A. Copland, PhD (basic science lead)
The paucity of effective therapeutic agents for hepatocellular cancer (HCC) despite decades of investigation underscores the critical need for more effective therapeutic strategies. Recent studies indicate lipid biosynthesis and desaturation is required for HCC survival. The increased metabolic needs of cancer cells in a setting of reduced nutrient availability underscore the importance of these pathways in cancer cell survival. Targeting these metabolic needs may prove beneficial because such changes can contribute to therapeutic resistance. As such, we seek to evaluate and therapeutically target a novel lipogenic tumor survival mechanism mediated by Stearoyl CoA desaturase (SCD1) as a means to combat the chemoresistance associated with HCC. In so doing, we will evaluate a novel lead SCD1 inhibitor singly, or in combination with other therapies, in relevant preclinical HCC mouse models, as a prelude to early phase clinical trials for HCC within the five-year SPORE funding period. We will also optimize efficacy and seek predictive biomarkers of response that could be clinically useful.
SCD1, a key mediator of fatty acid (FA) biosynthesis and rate-limiting in conversion of saturated fatty acids (SFAs) to mono-unsaturated fatty acids (MUFAs), is upregulated in HCC and many other cancers. Given that MUFAs can induce non-canonical autophagy (NCA), enhance membrane turnover, activate Wnts2 and increase energy production,3,4 enhanced conversion of SFAs to MUFAs by SCD1 can contribute to tumor cell survival. Inhibiting SCD1 by siRNA or a small molecule antagonist has been reported to have anti-tumor effects in HCC, and several other cancers,5-22 yet no therapies are being developed. Based on this and our exciting preliminary data, targeting tumor cell survival pathways that are mediated by SCD1 may be an effective therapeutic strategy for HCC. Furthermore, targeting NCA and Wnt signaling may be effective approaches to reducing cell survival under adverse conditions such as anticancer therapies, hypoxia/ischemia or nutrient deprivation.
Project 4: Viroimmunotherapy
Project Co-Leaders:
Richard G. Vile, PhD (basic science lead)
Lewis R. Roberts MB, ChB, PhD (clinical science lead)
Mitesh J. Borad, MD (clinical science lead)
Hepatocellular carcinoma (HCC) is diagnosed in more than 750,000 people worldwide annually, and is the second most frequent cause of death from cancer. Advanced-stage diagnosis and a paucity of effective therapeutic options has led to a 5-year survival rate below 12%.
Our group has conducted extensive preclinical characterization of engineered Vesicular Stomatitis Virus (VSV) as an oncolytic platform and has demonstrated it to be a highly effective immunotherapeutic agent for the treatment of cancer. This has led to the initiation of a Phase I first-in-human study of VSV expressing human interferon beta (hIFN-β) in patients with advanced sorafenib refractory/intolerant HCC. While clinical evaluation is ongoing and has shown preliminary evidence of efficacy with virus alone, our preclinical data supports the development of combinatorial therapy with complementary approaches to improve efficacy. We have established murine models which demonstrate that the combination of a systemic checkpoint inhibitor (CI) in conjunction with an intratumorally delivered oncolytic virus (OV) can significantly improve survival outcome over either modality alone, and that survival benefit is associated with a striking improvement in anti- tumor Th1 memory responses. In addition to the oncolytic effects of VSV, our lab has developed this platform as a potent vaccine vector that is capable of breaking tolerance to tumor-associated self-antigens (TAAs) in melanoma, prostate and glioma mouse models.
Our proposal is designed to build on the current pre-clinical understanding of VSV therapy in combination with checkpoint inhibition, as well as the ongoing clinical evaluation of VSV-hIFN-β, to design optimized treatment regimens using an in-situ vaccination approach. We hypothesize that oncolytic VSV provides a complementary mechanism of action to immune checkpoint inhibition and that this combination can be used to effectively treat HCC. This “bench to bedside and back” approach allows for the application of pre-clinical discoveries in clinical situations and their continuous refinement through further in vitro and in vivo modeling.
Administrative Core
Core Directors:
Mark A. McNiven, PhD
Lewis R. Roberts, MB, ChB, PhD
The Administrative Core provides infrastructure for managing finances, planning meetings, booking travel arrangements, and communications. The objective is to support the SPORE’s goals in general operations, in order for the SPORE to function more efficiently; this will allow the translational scientific goals to be achieved and advances in superior patient care to be attained.
Biostatistics and Bioinformatics Core
Core Directors:
Jun (Vivien) Yin, PhD
Chen Wang, PhD
The Biostatistics and Bioinformatics Core (Core B) provides statistical, bioinformatics, and computational biology collaboration and data management support for each of the Mayo Clinic SPORE in Hepatobiliary Cancers projects, developmental research and career enhancement projects, and shared resources cores. To ensure the overall goals of the SPORE are accomplished, Core B provides critical data management for clinical trials, monitor adverse events, and prepare data summaries for manuscript preparation. To that end, Core B works closely with the Administrative Core and Biospecimen and Pathology Core, ensuring a smooth continuum of data flow. Core B, one of the largest statistical groups in the country, builds upon the innovative and time- tested systems and procedures developed at Mayo Clinic.
Biospecimen and Pathology Core
Core Directors:
Lewis R. Roberts, MB, ChB, PhD
Michael S. Torbenson, MD
The Biospecimen and Pathology Core (Core C) is responsible for accessioning and processing new biospecimens with annotated clinical data to provide the needed biospecimens for the four SPORE translational research projects, for the Developmental Research and Career Enhancement Programs, and for other investigators engaged in hepatobiliary cancer research. Core C is built on the existing International Hepatobiliary Neoplasia Registry and Biorepository, which has been coordinated by Dr. Lewis Roberts since 2001, and collaborates with additional existing biorepositories including the Genetics of Cholestatic Liver Diseases Registry, coordinated by Dr. Konstantinos Lazaridis, the Liver Transplant Registry coordinated by Dr. Kymberly Watt, and the Hepatobiliary Neoplasia Patient Derived Xenograft program which is jointly coordinated by Dr. Mark Truty and Dr. Roberts. Core C also coordinates with The Fibrolamellar Hepatocellular Carcinoma Biorepository at the Rockefeller University under Dr. Sanford Simon. Core C provides sample accessioning and pathology support for the early phase clinical trials as needed in the SPORE projects and coordinates with the Mayo Clinic Cancer Center Biospecimen Accessioning and Processing (BAP) Shared Resource to process blood samples to genomic DNA and serum and plasma aliquots, and with the Pathology Research Core (PRC) Shared Resource to provide histology and other tissue-based services, including paraffin and frozen sectioning, immunohistochemistry, tissue microarray (TMA) construction, and digital imaging. Dr. Torbenson provides detailed annotation of the SPORE's tissue database for frozen and formalin-fixed paraffin-embedded tissues of all available patients who have had surgical resections for hepatobiliary cancer at Mayo Clinic, as well as for PDXs, a number of which are derived from percutaneous biopsies of patients with intermediate to advanced unresectable and metastatic disease. Dr. Torbenson also interprets IHC staining and provides other pathology support such as evaluating tumor samples from Sleeping Beauty, transgenic or knockout mouse models of liver and biliary cancer.
Developmental Research Program
Program Director:
Mark A. McNiven, PhD
The goal of the Mayo Clinic Hepatobiliary SPORE Developmental Research Program (DRP) is to attract, develop, support, and monitor the most promising and innovative projects pertaining to translational hepatobiliary cancer research, encouraging inter-disciplinary proposals so as to rapidly translate new treatment concepts to patients.
Career Enhancement Program
Program Director:
Lewis R. Roberts, MB, ChB, PhD
The Career Enhancement Program aims to provide integrated training and mentorship in the support of one new awardee per year. The program seeks to attract both early- or mid-career investigators who are new to hepatobiliary cancer and who will make a career commitment to translational research in this cancer.