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Last Updated: 08/15/19

Mayo Clinic, Rochester Hepatobiliary SPORE

Mayo Clinic, Rochester

Principal Investigators:
Mark McNiven, PhD
Lewis Roberts, MB, ChB, PhD


Mark A. McNiven, PhD
Mayo Clinic
Guggenheim Building, 16th Floor
200 First St. SW
Rochester, MN 55905
Phone: 507-284-0683
Fax: 507-284-2053

Lewis R. Roberts, MB, ChB, PhD
Hepatobiliary Cancer Laboratory
Mayo Clinic
Guggenheim Building, 17th Floor, Room 01
Mayo Clinic
200 First St. SW
Rochester, MN 55905
Phone: 507-266-3239
Fax: 507-284-0762


The Mayo Clinic SPORE in Hepatobiliary Cancer 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. 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 Hepatobiliar Cancer is supported by three cores to provide administrative, tissue, and data services to SPORE investigators. Additionally, the SPORE supports a number of innovative translational research projects through the Developmental Research Program and Career Enhancement Program, which supports junior faculty members.

Project 1: Fibrolamellar HCC

Project Co-Leaders:
Michael S. Torbenson, MD
Sanford M. Simon, PhD

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 in chromosome 19, a deletion that results in a chimeric gene. This work has now been reproduced at many institutions and the same deletion confirmed in every patient (n>280) in the absence of any other recurrent alterations in the DNA. 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.

The investigators have identified two specific aims: Aim 1 is to develop diagnostic tests as there are currently no specific non-invasive tests which are critical for early diagnosis and screening for recurrence. Two types of tests have been proposed: noninvasive blood tests and tests to provide a molecular diagnosis on biopsy samples. Each of these tests will be compared, double-blind, against conventional pathology diagnosis, which is currently based on a compatible H&E stain morphology, plus confirmatory immunostains or FISH testing. Aim 2 is focused on screening for compounds that block the activity of the chimera. The goal is to find a compound that selectively blocks the kinase activity of the FLHCC chimera. Such strategies have proven successful in treating other cancers with dysregulation of specific kinase activity. The investigators’ preliminary results utilizing SAXS, NMR and molecular dynamics simulations indicate distinct conformational states between the native PRKACA and the chimeric DNAJB1-PRKACA, encouraging a search for drugs that will selectively block the chimera.

Project 2: Therapeutic Inhibition of Fibroblast Growth Factor and YAP Signaling in Cholangiocarcinoma: Preclinical Studies and Clinical Trial

Project Co-Leaders:
Gregory J. Gores, M.D.
Mitesh Borad, M.D.

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. Project investigators aim to determine if disrupting these signals results in tumor cell death and therapeutic cancer regression in preclinical models in a proof-of-concept clinical trial. Both the Hippo and fibroblast growth factor receptor 2 (FGFR2) signaling pathways have been implicated as oncogenic mediators in cholangiocarcinoma. Investigators propose cross-talk between the Hippo and FGFR2 signaling pathways in cholangiocarcinoma. The team has generated preliminary data to demonstrate that FGFR2 signaling results in activation of the Hippo-effector protein, Yes-associated protein (YAP), a co-activator of transcription. 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.

The investigators have identified three specific aims based off of the hypotheses that: (i) YAP drives specific FGFR expression which in turn promotes YAP signaling, (ii) YAP nuclear localization serves as a biomarker for response to FGFR-targeted therapy, and (iii) inhibition of FGFR signaling is therapeutic in patients with CCA.

Project 3: Inhibition of SCD1 as a therapeutic strategy for HCC

Project Co-Leaders:
Tushar Patel, MB, ChB
John A. Copland, PhD

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. Stearyl CoA desaturase (SCD1) is a key mediator of fatty acid (FA) biosynthesis and is rate-limiting in conversion of saturated fatty acids (SFAs) to mono-unsaturated fatty acids. SCD1 is upregulated in HCC and many other cancers. The project investigators seek to evaluate and therapeutically target the novel lipogenic tumor survival mechanism mediated by SCD1 as a means to combat the chemoresistance associated with HCC. In so doing, the investigators 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. Project investigators will also optimize efficacy and seek predictive biomarkers of response that could be clinically useful.

Project 4: Immunovirotherapy

Project Co-Leaders:
Richard G. Vile, PhD
Lewis R. Roberts, MB, ChB, PhD
Mitesh J. Borad, MD

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%. Project investigators have 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. The investigators have established murine models which demonstrate that the combination of a systemic checkpoint inhibitor in conjunction with an intratumorally delivered oncolytic virus 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.

Project investigators 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. They will test this hypothesis by focusing on the following three Specific Aims: (i) Perform a Phase IB clinical study with an expansion cohort of VSV-hIFN-β in combination with the anti-PD-L1 antibody durvalumab in patients with advanced HCC, (ii) Using spontaneous models of HCC, determine the optimal dosing regimens of combination therapy with oncolytic VSV-IFN-β, and (iii) Develop a next generation VSV platform expressing TAAs that are specifically tailored to HCC.

Administrative Core

Core Directors:
Mark A. McNiven, PhD
Lewis R. Roberts, MB, ChB, PhD

The goal of the Administrative Core of the Hepatobiliary Cancers SPORE is to facilitate a well- organized, well-executed program, providing responsible time and fiscal management. The Core will also play the lead role in maintaining continuous communication within the program, supporting relationships across projects and cores. It will also serve as the link to NCI program oversight, contact among other SPORES across the U.S., and collaboration and resource sharing within Mayo Clinic’s SPORE programs.

The Administrative Core’s specific aims are to: 1) Provide leadership and facilitate collaboration between the Research Projects and Cores of the SPORE, 2) Assure incorporation and participation of the Hepatobiliary Cancer SPORE in the activities of the Mayo Clinic Cancer Center, 3) Establish monthly meetings of SPORE investigators and the Internal Advisory Board, 4) Arrange yearly SPORE research retreats and 2x/year meetings with the External Advisory Board, 5) Coordinate monthly meetings of the Mayo Clinic Cancer Center SPORE Directors’ Working Group as needed, 6) Provide administrative support to the Developmental Research Program and the Career Enhancement Program, 7) Facilitate investigator trips to relevant SPORE meetings, 8) Enable activities of the Hepatobiliary Cancer SPORE advocates, 9) Prepare the yearly non-competing SPORE application, 10) Serve as the administrative liaison between the Mayo Clinic SPORE and the NCI SPORE Program, other SPOREs, and collateral organizations 11) Maintain the Mayo Hepatobiliary Cancer SPORE Websites that will be useful to investigators inside and outside the SPORE, as well as patients 12) Coordinate information and communication about SPORE research developments to the Mayo Clinic SPORE investigators, the scientific community at large, and the public.

Biostatistics and Bioinformatics Core

Core Leaders:
Sumithra J. Mandrekar, PhD
Chen Wang, PhD
Vivien Yin, PhD

The Biostatistics and Bioinformatics Core (BBC) will provide statistical, bioinformatics, and computational biology collaboration and data management support for each of the Mayo Clinic SPORE in Hepatobiliary Cancers (HBCs) projects, developmental research and career enhancement projects, and shared resources cores. These essential services are centralized in the BBC to ensure biostatistical and bioinformatics activities are performed in a cost effective and coordinated manner. The BBC has been active in preparing the statistical plan related to study design, analysis, and bioinformatics needs for each of the four HBCs projects. To ensure the overall goals of the SPORE are accomplished, the BBC will provide critical data management for clinical trials, monitor adverse events, and prepare data summaries for manuscript preparation. To that end, the BBC will work closely with the HBCs Administrative Core and Biospecimen and Pathology Core, ensuring a smooth continuum of data flow, especially as clinical trials are undertaken. The BBC, one of the largest statistical groups in the country, builds upon the innovative and time- tested systems and procedures developed at Mayo Clinic. The BBC will also utilize many of the shared resources supported by the Mayo Clinic Cancer Center (MCCC) and from additional institutional cores and resource units.

The BBC’s Specific Aims are to: 1) Provide statistical and bioinformatics collaboration for each of the SPORE projects, Developmental research projects, Career Enhancement Program projects and cores, 2) Provide management and integration of existing and newly collected data through consistent and compatible data handling, and 3) Provide support to the Biospecimens and Pathology Core in providing resources to the research community.

Biospecimen and Pathology Core

Core Directors:
Michael S. Torbenson, MD
Mark J. Truty, MD, MS
Lewis R. Roberts, MB, ChB, PhD

The Overarching Goal of the Mayo Clinic Hepatobiliary SPORE Biospecimen and Pathology Core will be the development, annotation, and maintenance of a human cancer site-specific specimen resource, including linkage of specimens with pre-analytical parameters and pathological, clinical, and family history data that maximize their potential use in translational research for use by SPORE Projects. The Biospecimen and Pathology Core will be building on the existing infrastructure of the International Hepatobiliary Neoplasia Registry and Biorepository (IHNB), coordinated by Hepatobiliary SPORE Co-PI Lewis R. Roberts, M.B., Ch.B., Ph.D.

The Biospecimen and Pathology core collaborates with other hepatobiliary repositories, including coordination with the fibrolamellar hepatocellular carcinoma resources that have been assembled by Dr. Sanford Simon at the Rockefeller University.

The goal of the Biospecimen and Pathology Core will be to provide investigators in the Hepatobiliary Cancer SPORE access to high quality patient data, DNA, plasma, serum, and liver and biliary cancer tissue biospecimens and patient derived xenografts from consented hepatobiliary cancer patients and to make these resources available for the four main SPORE Projects (described in detail in Section X.4), for future Developmental Research Program (DRP) and Career Enhancement Program (CEP) research projects, and for other institutional and collaborating investigators as feasible.

The Specific Aims are: 1) to provide clinically annotated blood-derived specimens 2) to provide clinically annotated frozen and formalin-fixed tissue specimens, histopathologic characterization, and histology-related laboratory-based services, and 3) to provide clinically annotated patient derived xenografts (PDXs), cell lines and other animal models.


Edward B. Leof, 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 that have the greatest potential to be translated into clinically important applications to reduce the morbidity and mortality of hepatobiliary cancer.

The specific aims of the Developmental Research Program are to: 1) Solicit and support innovative and interdisciplinary translationally-relevant laboratory, population science, and clinical studies in hepatobiliary cancer, 2) Encourage the recruitment of qualified minorities, women, and persons with disabilities, 3) Provide critical evaluation of all DRP applications and awardee progress, and 4) Facilitate the development of DRP-funded proposals into RO1-level applications and/or future SPORE projects.

The Hepatobiliary SPORE’s Internal Scientific Advisory Committee conducts a rigorous peer-review process to evaluate all program applications based on scientific merit, originality, applicant and co-investigator qualifications, and translational potential.

Support from the Developmental Research Program is expected to result in the generation of data to serve as the basis for additional Hepatobiliary SPORE-sponsored projects or support through other external peer-reviewed mechanisms.


Lewis R. Roberts, MB, ChB, PhD

The Mayo Clinic SPORE in Hepatobiliary Cancers (HBC) aims to mentor junior faculty seeking to develop independent research programs in translational HBC research and mid-career applicants who wish to refocus their research trajectory on HBC. As there is a need for experienced investigators who can more rapidly realize gains in addressing this devastating disease, it is critically important to inspire and attract individuals who are at an important juncture in defining their research programs.

By blending patient care with basic and applied research facilities, Mayo Clinic provides an environment conducive to translational research. Through the integration of our CEP for junior and early mid-career faculty with our existing core of committed and experienced HBC researchers, and a highly productive team of investigators in other areas of cancer research who can serve as co-mentors, an exciting diversity of research approaches to address the morbidity and mortality of HBC will be generated.

The CEP is structured on the following Specific Aims: 1) Identify the most promising candidates. Construct an outreach, recruitment, and identification process that cast an effective net to draw on promising investigators, 2) Emphasize the recruitment of qualified women, minorities, and persons with disabilities. Leadership will partner with a number of diversity-related departments and programs within Mayo Clinic to recruit talented individuals from historically underserved populations, 3) Conduct a thorough selection process for all CEP applicants. The CEP work with the current six Mayo SPORE CEPs for guidance to develop its vetting process. It will also rely on a strong review team to carry out processes, 4) Effectively mentor, monitor, and evaluate awardees. CEP leadership will develop a continuous process for supporting awardees to succeed in the program. The goal is to ensure a consistent architecture of oversight capable of meeting each investigator’s needs, and 5) Facilitate extramural funding for and integration of awardees into future SPORE projects. The CEP will draw on several Mayo Clinic resources that are directed at supporting funding identification and proposal development.