Research Status and Funded Projects

Current research status

Since 2010 FCF has committed over $8 million to research, with the goal to accelerate the development of curative therapies. This research has been led by respected MD’s and PhD’s and includes clinical trials, translational, and basic research.

In the following video from FCF’s September 2020 Virtual Fall Gathering, Mark Furth, FCF’s Scientific Director, discusses the current state of research in FLC.

Video overview of FCF’s research program. Please see our YouTube channel for other related presentations and panel discussions.

Research funding levels

The following charts summarize the research grants awarded and committed by category and institution. FCF is grateful for the generous gifts from donor that make this important work possible. 100% of donated funds are used to directly support research efforts.

FCF Funded Projects

The following is a brief summary of the active and completed projects in each research priority area:

  • Massachusetts General Hospital
    Fibrolamellar Carcinoma Model Development and Analysis
    2019 – 2021

    Goal: Model development

    Principal Investigator: Nabeel Bardeesy, PhD, Associate Professor, Massachusetts General Hospital, Harvard University

    Multiple FLC models have recently been developed, which have advanced our understanding of this disease. However, additional model development remains a priority for the FLC community. We aim to develop multiple different FLC models as resources for the FLC research fibrolamellar cancer research community. We will collaborate with the Fibrolamellar Cancer BioBank established at Massachusetts General Hospital to obtain biological specimens. These specimens will be used to create series of transplant human FLC tumors grown in immune-deficient mice (patient-derived xenograft [PDX] models), three-dimensional cell culture models (3D tumor organoids), and cell lines in partnership with the Broad Institute.

    Together with collaborators at the Broad Institute and throughout the FCF research network, we will harness these newly developed models to identify genetic dependencies and drug sensitivities of the disease. (Please also see the Broad Institute initiative). Additional studies will be aimed at further understanding this cancer by examining gene expression at the single cell level and characterizing non-cancerous cells that support or interact with tumor cells such as immune cells and stromal cells that make up the characteristic fibrous bands for which fibrolamellar carcinoma was named. Our studies aim to better understand the molecular mechanisms underlying FLC formation and growth and ultimately will set the stage for the development of new therapeutics.
  • Boston Children’s Hospital
    Development of a Human-Derived Liver Progenitor Cell Line with DNAJB1-PRKACA Fusion Gene
    2019 – 2020

    Goal: Development of a novel human-derived liver progenitor cell line model of fibrolamellar carcinoma

    Principal Investigator: Khashayar Vakili, MD, Surgical Director of Liver, Kidney, Intestine, and Multivisceral Transplant Programs, Assistant Professor of Surgery, Harvard Medical School

    In our lab, we have engineered a kidney cell line (HEK-DP) which contains the DNAJB1-PRKACA fusion gene found in FLC tumors. This cell line demonstrates interesting similarities to FLC tumors and serves as a proof of concept for the development of additional cell lines. We will apply the same strategy used to engineer the HEK-DP model to engineer normal human liver progenitor cells to express the DNAJB1-PRKACA fusion gene. These liver progenitor cells will be grown as three-dimensional “organoid” cultures to better replicate in vivo conditions. This novel model will allow us to understand how the fusion protein reprograms normal liver progenitor cells to become cancerous. Understanding the precise mechanisms underlying the formation of FLC will provide insights to future therapeutic strategies.
  • University of Wisconsin/Cancer Research Institute
    Role of the innate immune system in Fibrolamellar Hepatocellular Carcinoma (FL-HCC) using zebrafish as a model system
    2016 – 2019

    Goal: Use zebrafish as a model system for fibrolamellar carcinoma to study the immune system

    Principal Investigator: Sofia de Oliveira, Ph.D., EMBO Postdoctoral Fellow, Huttenlocher Immunology Lab

    Few FLC animal models currently exist limiting our ability to study FLC in the context of a complete organism. While cell-based models are extremely useful, animal models allow scientists to study biological processes involving multiple organs and cell types, such as tumor immunology and metastasis. Zebrafish are a valuable tool to study many diseases including cancer and have been used as a model system by the genetics community for decades. They display remarkable similarities and share many genetic signatures with humans and have been used to study liver development, hepatocellular carcinoma, and several other liver disorders. We plan on developing a zebrafish model of FLC and harnessing this model to study how the immune system interacts with FLC. We will investigate the role of various immune cells in FLC and assess their potential as therapeutic targets for FLC.
  • Stanford University
    Developing pre-clinical models for fibrolamellar FL-HCC: Therapeutic target identification and testing
    2016 – 2018

    Goal: Develop a pre-clinical mouse model for fibrolamellar carcinoma

    Principal Investigator: Dr. Julien Sage, Ph.D., Associate Professor, Department of Pediatrics and Genetics

    There are few effective therapies for FLC patients and development of improved therapeutics are hampered by the rarity of the disease and the challenge of including pediatric patients in many clinical trials. One solution to this problem is the development of accurate models of FLC. We propose to generate a mouse model for FLC. Because FLC occurs primarily in children and young adults, we hypothesize that the expression of the DnaJ-PKA fusion found in FLC tumors cells initiates cancer in specific liver stem/progenitor cell populations during development. Using genetic engineering techniques, we will introduce the DnaJ-PKA fusion into the mouse genome in an inducible manner. Therefore, we will be able to switch on expression of DnaJ-PKA at specific stages of liver development to examine exactly how this fusion contributes for FLC formation. These mouse models will also provide a novel preclinical platform to test future therapeutic strategies.

    For additional details see the article published by Stanford on FCF’s grant and collaboration.
  • Johns Hopkins University
    Blood markers for fibrolamellar
    2010

    Goal: Identify biomarkers

    Principal Investigator: Michael Torbenson, MD, Department of Pathology, Johns Hopkins University (Currently at Mayo Clinic)

    Early identification of tumors is essential for aggressive treatment. The majority of fibrolamellar carcinoma (FLC) patients have metastatic disease at the time of diagnosis. Therefore, identification of biomarkers for FLC is essential. Using a broad collection of FLC pathology specimens, we plan to identify diagnostic biomarkers for FLC. Furthermore, we will investigate whether these biomarkers are linked to any genetic mutations or microRNA expression profiles unique to FLC.
  • Broad Institute of MIT and Harvard
    Creating a Fibrolamellar Cancer Dependency Map
    2020 – 2022

    Goal: Create a comprehensive list of potential drug targets for FLC

    Principal Investigator: Jesse Boehm, PhD, Institute Scientist, Director of the Broad Cancer Model Development Center

    This project is part of the Broad Institute’s Rare Cancer Dependency Map Initiative. Our project has three main goals to identify potential FLC therapeutics. First, we will develop new cell models of FLC for the research community. Harnessing the Broad Institute’s Cancer Cell Line Factory laboratory and its combinatorial media screening technology will allow us to systematically determine the conditions necessary to grow FLC samples as three-dimensional organoid models. We will also work in coordination with the FCF-sponsored BioBank to create a unified pipeline by which any patient can direct tissue to FLC researchers. Second, we will utilize our cell culture models of FLC to create a comprehensive list of potential drug targets and to identify existing drugs that may have therapeutic potential against FLC. Third, we will empower the entire FLC research community by sharing our genomically characterized and clinically annotated cell models and by making all the data and biologist-friendly analysis tools freely available online, pre-publication at DepMap.org.
  • Cornell University
    Micro RNAs and long non-coding RNAs role in fibrolamellar and evaluation of RNA-based therapeutics
    2017 – Current

    Goal: Investigate the role of microRNAs and long non-coding RNAs in fibrolamellar carcinoma and evaluate RNA-based therapeutics

    Principal Investigator: Praveen Sethupathy Associate Professor Department of Biomedical Sciences, Cornell University, College of Veterinary Medicine

    Our group aims to leverage genome-scale approaches to discover the molecular factors most critical to FLC tumor formation, metastasis, and drug resistance. MicroRNAs and long non-coding RNAs are RNA species that do not contain instructions for protein formation yet are vital to numerous biological processes including tumor formation. We aim to identify microRNAs and long non-coding RNAs that facilitate FLC tumor formation/invasion and evaluate the potential of RNA-based therapeutics to inhibit their activity. Integration of these results with multiple large-scale genomic and metabolomic datasets will allow us to identify critical druggable pathways. We are actively engaged in collaborative ventures that bring together researchers with a shared commitment to tackle this devastating disease and bring relief and hope for patients.

    For a description of some of our recently published work, we encourage you to visit here <https://www.cmghjournal.org/article/S2352-345X(19)30010-4/fulltext> and here<http://news.cornell.edu/stories/2019/02/key-rare-aggressive-liver-cancer-found-rna-molecule>.
  • University of California San Francisco and Harvard University
    Targeting DNAJB1-PRKACA Driven Signaling Dependencies in Fibrolamellar Liver Cancer
    2019 – 2021

    Goal: Investigate the potential of AURKA inhibitors for FLC treatment

    Principal Investigator: John Gordan, MD, PhD, Assistant Professor, Department of Medicine, UCSF

    Co-Investigator: Nabeel Bardeesy, Associate Professor, Massachusetts General Hospital, Harvard University

    Even though the DNAJB1-PRKACA gene fusion (encoding a chimeric protein with a domain of heat shock protein 40, HSP40, fused to a majority of the enzymatically active subunit of protein kinase A, PKAc) is sufficient to trigger fibrolamellar liver cancer (FLC), no treatments directed at this target are clinically available. Most FLC patients receive chemotherapy and no PKA inhibitors are currently in clinical use.

    Over the past two years, we have mapped the signaling cascade downstream of PRKACA in FLC and other tumors (link to project below). This analysis highlights Aurora Kinase A (AURKA) as a key mediator of oncogenic growth. AURKA is best known for regulating the cell cycle, but also promotes cell survival and the expression of oncogenic genes (i.e., those that contribute to cancerous growth). Most conventional AURKA inhibitors fail to strongly inhibit the growth of human FLC cells. This finding is consistent with limited activity observed with such a drug in clinical trials. However, colleagues at UCSF described a novel class of AURKA inhibitors designed to disrupt its interaction with members of the MYC family of oncoproteins, which are critical drivers of many cancers. We find that one of these new AURKA inhibitors does potently reduce proliferation of FLC cells. The drug also reduces expression of MYC-family oncogenic transcription factors. We hypothesize that AURKA-mediated stabilization of MYC is necessary to maintain growth of FLC cancer cells. Although these new AURKA inhibitors are not yet ready for human use, by studying them we can understand if they are likely to be effective for FLC and whether they work well in combination with other available drugs. We plan to assess the activity and mechanism of conformation disrupting AURKA inhibitors in FLC laboratory models, including human tumors grown in mice, with the goal of identifying a drug in this class that could be advanced to clinical testing in FLC patients.
  • Molecular Therapies for Fibrolamellar Carcinoma (FLC)
    2019 – 2021

    Goal: Investigate the potential of heat shock protein 70 (Hsp70) and mitogen-activated protein kinases (MAPKs) as therapeutic options for FLC

    Principal Investigator: John Scott, PhD, Edwin G. Krebs-Speights Professor of Cell Signaling and Cancer Biology, and Chair, Department of Pharmacology

    Precision medicine approaches have identified the underlying genetic defect in FLC as a deletion in chromosome 19. Consequently, FLC patients produce a unique protein in which an important part of heat shock protein 40 (DNAJ) is fused to a key cellular enzyme called protein kinase A (PKAc). This chimeric protein, DNAJ-PKAc, is expressed in FLC tumors where it hijacks normal cellular processes, leading to cancer.

    We believe that DNAJ-PKAc brings together unique combinations of cellular enzymes that cause FLC. These protein complexes activate the biochemical pathway downstream from the fusion protein, deregulating cell proliferation. Thus, drugs that target such key protein combinations represent a therapeutic opportunity. We have discovered drug pairs that halt the growth of genetically modified liver cells that mimic the human cancer. Our experimental plan is to test a new concept in drug treatments for FLC. Rather than blocking the action of the DNAJ-PKAc protein kinase enzyme itself, we will use combinations of FDA-approved drugs and/or drugs already in clinical testing that neutralize proteins associated with this chimeric enzyme. In particular we believe that combinations of drugs targeting proteins that bind tightly to DNAJ-PKAc, such as heat shock protein 70 (Hsp70) and mitogen-activated protein kinases (MAPKs), will offer a viable therapeutic option. This pharmacological approach and the use of repurposed FDA-approved drugs will expedite a cure for FLC.
  • Retinoic Acid-Induced Loss of DNAJB1-PRKACA Fusion Protein Expression
    2019-2020

    Goal: Investigate the potential of retinoic acid therapy

    Principal Investigator: Andrew Yen, PhD, Professor, Department of Biomedical Sciences

    Co-Principal Investigator: Praveen Sethupathy, PhD, Associate Professor, Department of Biomedical Sciences

    FLC is driven by the DNAJ-PKAc fusion protein. A potential therapeutic strategy would be to induce loss of this key driver protein. One approach to substantially alter gene expression in cancer cells is differentiation induction therapy, which causes malignant cells to acquire more mature, specialized characteristics and to stop proliferating. The most successful differentiation therapy agent in current use is retinoic acid (RA), which has been the standard of care for acute promyelocytic leukemia (APL). RA, a metabolite of Vitamin A, induces APL cells to convert from a proliferating malignant state resembling immature white blood cells to a non-transformed, arrested state resembling the corresponding normal, mature white blood cells. Our preliminary observations in a model cell line engineered to stably express DNAJ-PKAc showed that RA causes loss of the fusion protein. We now will assess whether RA similarly decreases the level of DNAJ-PKAc in cultured human FLC cells and determine the optimal concentration and duration of RA treatment.
  • Hedgehog and YAP signaling in fibrolamellar carcinoma: Tumor-stroma crosstalk and the cancer stem cell niche
    2017 – 2019

    Goal: Evaluate the role of Hedgehog and YAP signaling in fibrolamellar carcinoma

    Principal Investigators: Cynthia Guy, MD, Associate Professor of Pathology; Anna Mae Diehl, MD, Florence McAlister Professor of Medicine, Duke University School of Medicine

    Fibrolamellar carcinoma has a unique histological appearance consisting of large tumor cells surrounded by thick fibrous bands, the stroma. Molecular crosstalk between tumor and stroma is important in tumor maintenance and progression. Decoding the important signals in these interactions will reveal new potential therapeutic targets. We aim to study the role of Hedgehog (Hh) signaling in tumor-stromal interactions. Hh signaling is important in normal liver development and regeneration as well as tumor-stromal interactions in other cancers. Active Hh signaling also activates a protein called Yap, which results in stroma accumulation and primitive stem cells, both of which are seen in FLC. We will examine the role of Hh and Yap signaling in tumor-stroma interactions and their effect on tumor growth and progression.
  • Mayo Clinic
    Kinase fusion function investigation
    2016 – 2018

    Goal: Investigate DNAJB1-PRKACA fusion kinase function in new fibrolamellar carcinoma models

    Principal Investigator: Dr. Yi Guo, Ph.D, Associate Consultant – Asst Professor, Dept of Biochemistry and Molecular Biology

    The DNAJB1-PRKACA fusion kinase is found in nearly 100% of FLC cases. While this novel fusion has been shown to promote tumors in mice, defining the mechanistic function of DNAJB1-PRKACA and the pathways it controls is critical for the development of targeted therapeutics. Our group will investigate the function of the DNAJB1-PRKACA fusion in FLC tumor formation using both Drosophila melanogaster (fruit fly) and mice models. We have established a DNAJB1-PRKACA transgenic Drosophila model, in which the fusion is expressed in the eye where phenotypes are easily visible. This model demonstrates abnormal phenotypes affecting both proliferation and differentiation of Drosophila eyes. We also exploited CRISPR/Cas9 genome-engineering technology in murine cultured hepatocytes to recreate the endogenous chromosomal deletion found in FLC patients. We plan to 1) characterize the oncogenic and fibrogenic activities of genetic engineered murine hepatocytes in vitro and in vivo; and 2) screen potential therapeutics using the DNAJB1-PRKACA over-expression model in Drosophila. Our study will provide essential resources and knowledge for future development of new FLC therapeutics.
  • University of Vermont
    Characterizing enzyme inhibition of the DnaJPKAc chimeric protein derived from fibrolamellar hepatocellular carcinomas
    2017 – 2019

    Goal: Characterize inhibition of the DnaJ-PKAc chimeric protein in fibrolamellar carcinoma

    Principal Investigator: Hibba tul Rehman, M.D., University of Vermont

    The DNAJB1-PRKACA fusion gene produces the DnaJ-PKAc fusion kinase protein, which is present in nearly all FLC tumors and promotes liver tumor formation in mice. Kinases, including fusion kinases, have been successful drug targets in numerous cancer types. Inhibition of DnaJ-PKAc may provide the first targeted therapy for FLC. We propose a two pronged approach towards identifying therapeutic inhibitors of the fusion. First, we will screen a previously developed peptide library to identify peptides that preferentially bind chimeric DnaJ-PKAc over normal, wide-type protein in vitro. Second, we will develop a library of inhibitory peptides that would preferentially inhibit DnaJ-PKAc. These studies will allow us to develop inhibitors that regulate the function of the chimeric kinase without affecting the wild-type kinase, thus selectively targeting cancer cells without affecting healthy tissue.
  • University of California San Francisco and Harvard University
    Flipping the switch on PKA: synthetic lethal approaches to block PKA-driven tumor growth in fibrolamellar liver cancer
    2016 – 2019

    Goal: Understand growth mechanisms and identify potential therapeutic targets

    Principal Investigators: John Gordan. M.D., Ph.D, Clinical Instructor, University of California San Francisco; Nabeel Bardeesy, Ph.D, Associate Professor, Harvard University

    The discovery of a genetic change in the protein kinase A (PKA) gene in nearly all cases of fibrolamellar liver cancer (FLC) creates hope that targeted therapy against PKA will have potent effects for FLC patients. However, progress has been limited due to the relative scarcity of established model systems and the current lack of an effective anti-PKA drug. PKA is a component of the G protein-coupled receptor (GPCR) pathway, which is thought to play a role in many other cancer types. However, little is known about how this pathway makes tumors grow, and if it creates any specific liabilities in tumor cells that can be effectively targeted even when PKA is still active. We hypothesize that common mechanisms support the growth of different cancers where PKA is abnormally activated and that deciphering these mechanisms will lead to new treatment strategies for FLC.

    We will apply cutting-edge proteomic methods to comprehensively map biochemical processes controlled by GPCRs and PKA across a number of cancer cell lines. We will complement these efforts with genetic approaches to identify other genes that are essential for PKA-driven cancer growth. Finally, we will use newly developed FLC models to test key targets identified with our screening techniques. By identifying and rigorously testing the importance of the mediators of PKA signaling in FLC, we will be positioned to repurpose existing drugs to accelerate progress in the treatment of patients with FLC.
  • University of Washington
    Therapeutic Innovations in Fibrolamellar Cancer
    2017 – 2019

    Goal: Understand growth mechanisms and identify potential therapeutic targets

    Principal Investigator: Raymond Yeung, MD, Professor of Surgery

    Fibrolamellar cancer (FLC) is the most lethal form of liver cancer in adolescents and young adults. Currently, there is no effective therapy for these patients besides surgery. With the identification of a unique genetic defect that affects nearly all FLCs (the DNAJB1-PRKACA gene fusion), the opportunity to find a cure for this disease is now within reach. Armed with a novel set of immortalized cell lines developed at the University of Washington that bear the FLC mutation, we will advance our understanding of the mechanisms that drive FLC development. Firstly, we will identify protein kinase pathways that are activated downstream of the mutation using a combination of global and targeted phosphoproteomic analyses. These results will be functionally validated using our FLC cell lines as well as human FLC samples. Secondly, based on our preliminary observations that the mutant protein associates with heat shock protein (HSP) 70, we will investigate the role of HSPs in FLC, including their pro-survival function in keeping cells alive during stress. Together, our proposed studies will unveil mechanistic insights and new therapeutic targets that will bring us closer towards a cure for this deadly disease.
  • Rockefeller University
    Developing Therapeutics for Fibrolamellar Hepatocellular Carcinoma
    2016 – 2017

    Goal: Develop new therapeutics for FLC

    Principal Investigator: Sandy Simon, Ph.D., Professor
    Investigator Collaboration: Barbara A. Lyons, Ph.D., Professor, New Mexico State University

    The goal of our work is to develop therapeutics for FLC. We have three independent strategies based on our laboratory’s work showing that a single common DNA alteration is found in all fibrolamellar tumors leading to the DNAJB1-PRKACA fusion and that this chimera is sufficient to cause fibrolamellar. The first project is a high-throughput screen for molecules that directly block the chimera. This screen will cover millions of compounds with no prior assumptions about which compounds might work. The second project is a screen to identify molecules that are directly phosphorylated by the chimera. The third project is an analysis of the structural dynamics of the chimera using a molecular dynamics simulation. This project is based on unpublished x-ray and NMR data on the structure of the chimera, together with molecular dynamics simulations, to identify sites on the chimera that would be appropriate for targeting therapeutics.
  • Rockefeller University
    Discovery of the chimera genetic mutation
    2014 – 2015

    Goal: Identify genetic mutations in FLC

    Principal Investigator: Sandy Simon, Ph.D., Professor, Rockefeller University

    The goal of this project is to identify genetic mutations present in FLC. We will use whole genome sequencing together with RNA sequencing to identify mutations in FLC tumors compared to their normal liver counterparts. Identification of mutations common in FLC tumors will enhance our understanding of the underlying biology of this tumor and allow for development of novel therapeutics. Our research ultimately resulted in game-changing discovery of a unique genetic mutation, a chimeric gene, common to all fibrolamellar tissues studied. This research was conducted at the Tucker Davis Research Facility at Rockefeller University, led by Dr. Sandy Simon. His daughter Elana, who is a fibrolamellar patient, was a lead researcher. The results were published in the preeminent medical journal Science and reported in The Wall Street Journal, US News and World Report, AP, The Today Show, NBC Nightly News, and presented to President Obama.
  • Yale University
    Iodine Transporter Research
    2014 – 2015

    Goal: Investigate the potential of radioactive iodine as a therapeutic in FLC

    Principle Investigator: Nancy Carrasco, MD, Professor, Cellular and Molecular Physiology, Yale University (Currently at Vanderbilt University)

    FLC cells express high levels of the iodine transporter NIS, raising the possibility that radioactive iodine may be a potential therapeutic for FLC. Radioactive iodine has a long and effective history as a treatment for thyroid cancer, which effectively takes in iodine. We will investigate whether FLC cells readily uptake iodine and if radioactive iodine may serve as an effective therapeutic for FLC patients.

    [NOTE:  Use of radioactive iodine on several patients did not confirm this theory and the project was terminated]
  • University of British Columbia
    MicroRNA research support
    2011

    Goal: Profile microRNA in metastatic Fibrolamellar Carcinoma

    Principal Investigator: Yuzhou Wang, PhD, University of British Columbia

    MicroRNAs are small RNA species that regulate the expression of other genes and are important in many biological processes, including tumor development, growth, and metastasis. MicroRNAs have become increasingly useful as diagnostic markers, prognostic indicators, and therapeutic targets. We plan on examining the microRNA profile of FLC tumors which metastasize and matched tumors that do not metastasize. By identifying microRNAs that may predict or lead to tumor metastasis, our results may help to create new diagnostic and therapeutic tools and strategies.
  • Cancer Research Institute (CRI) Partnership

    Goal: Develop and fund three-year FLC research fellowships

    CRFCF has partnered with the prestigious Cancer Research Institute (CRI) to specifically focus on the role immunotherapy may have in creating curative therapies for fibrolamellar. CRI has been promoting immunotherapy research for 65 years, long before the establishment cancer treatment and research community recognized immunotherapy as a legitimate prospect for cancer patients.

    For the past several years, FCF has worked with CRI to develop, staff and fund prestigious three-year research fellowships. The young researchers awarded these fellowships have been making great strides forward in investigating the applicability of immunotherapy to FLC treatment.
  • Modulating stromal-immune cell interactions to activate anti-tumor immunity to fibrolamellar carcinoma
    2019 -2020

    Goal:
    Assess whether supressing checkpoints or signaling by a specific chemokine (CXCL12) can enhance immune response

    Principal Investigator: Venu Pillarisetty, MD, Associate Professor, Division of General Surgery [Extension after CRI Fellowship grant to Kevin Sullivan in Dr. Pillarisetty’s lab, 2016-2019]

    Immunotherapy, harnessing the patient’s immune system to precisely target cancer cells, has emerged as a promising approach to treat many cancers. We and others have found that fibrolamellar carcinoma (FLC) tumors contain a class of immune cells called T cells that potentially could recognize and destroy the cancer cells. However, the therapeutic ability of T cells can be limited by suppressive factors made by both cancer cells and other cells in the tumor such as the abundant fibroblastic stromal cells that give FLC its name. Suppressive molecules in the tumor microenvironment that may limit anti-cancer immune responses include “immune checkpoints” and signaling molecules known as cytokines. The latter include chemokines, small protein chemical messengers that influence cell migration. We will determine whether blockade of checkpoints and/or signaling by a specific chemokine (CXCL12) can enhance T cell mediated immunity against fibrolamellar cancer cells, using slice cultures of human FLC tumors.
  • University of Washington
    T cell immunotherapy in fibrolamellar cancer
    2016 – 2019

    Goal: Characterize T-cells in the FLC tumor microenvironment

    Principal Investigator: Kevin M. Sullivan, M.D., General Surgery

    Immunotherapy is a form of cancer treatment that harnesses the patient’s own immune system to fight the disease. The immune system can precisely target cancer cells, while also minimizing damage to the remainder of the body’s normal cells. In this project, we will investigate a well-established method of using the immune system, successful in treating other cancers such as melanoma, as a treatment for fibrolamellar. We will start by using a variety of techniques to look at which types of immune cells reside within fibrolamellar tumors. One type of immune cell, called the T cell, is of particular interest because it can specifically recognize and destroy cancer cells. Our group has previously confirmed that T cells are found within fibrolamellar tumors. We will gain a detailed understanding of the characteristics of the T cells that are active within fibrolamellar tumors. We then plan to grow and activate these T cells and test their ability to fight cancer cells in cell cultures and slices of fibrolamellar tumor grown in the laboratory. Ultimately, our project will provide the basis for making T cell immunotherapy against fibrolamellar a reality.
  • Johns Hopkins University
    Investigating immune checkpoint biomarkers in tissue and peripheral blood of patients with fibrolamellar hepatocellular carcinoma
    2016 – 2019

    Goal: Define the dominant immune checkpoint pathway in FLC

    Principal investigator: Amy K. Kim, M.D., Assistant Professor

    Tumor cells produce immune checkpoint molecules that suppress host immune response and allow evasion from immune responses. The discovery of drugs that block these immune checkpoints have revolutionized current cancer treatment. Anti-PD1 (programmed cell death protein 1) immunotherapy has shown benefit in many cancer types, but certain cancers have also shown strong resistance to this immunotherapy. It is unclear how fibrolamellar carcinoma would respond to different immune checkpoint blockades, including anti-PD1 therapy. In addition, it is unclear how circulating tumor cells (CTCs) in the blood that have disseminated from the primary tumor induce anti-tumor immune response outside the tumor environment.

    We will address these unknown issues by: 1) defining the dominant immune checkpoint pathway in fibrolamellar cancer and its interaction with the patient’s immune response in the tumor, and 2) determining how immune checkpoint markers are associated with circulating tumor cells in the peripheral blood, in comparison to the primary tumor. Understanding the immune checkpoint landscape in fibrolamellar carcinoma will guide the development of future immunotherapies for this deadly cancer.
  • Pre-clinical studies of the interactions of the immune system with FL-HCC
    2016 – 2019

    Goal: Study the interactions between the immune system and FLC in a mouse model

    Principal Investigator: Kevin Barry, Ph.D., Postdoctoral Scholar

    Cancer immunotherapies harness the power of the immune system to kill tumors. Checkpoint blockade immunotherapies are an exciting class of cancer immunotherapies that remove the brakes from the immune system and allow effective killing of tumor cells. These therapies function by targeting molecules that inhibit tumor-directed responses by immune cells called T cells. T cells are important for protecting patients from tumors as these cells directly kill tumor cells and modulate the global immune response towards tumors. Immunotherapies targeting T cells have been remarkably effective in treating non-FLC cancer patients, leading to tumor regression and offering long-term protection, effectively providing a cure to cancer in some patients. However, very little is known about how the immune system interacts with FLC or if immunotherapy would be an effective treatment for FLC.

    The study of the efficacy of immunotherapy in the treatment of FLC is hampered by the fact that the current patient-derived xenograft animal models of FLC utilize the transplantation of human tumor into immune compromised animals.
    The lack of an effective immune system allows the host mice to grow tumors, but also makes it impossible to study the interactions between the immune system and FLC in this model system. We will harness a preclinical mouse model of FLC developed by Dr. Julien Sage and Stanford University with a fully functional immune system to understand how the immune system interacts with FLC. These studies represent the first step in moving towards treating FLC patients with immunotherapy in the clinic.
  • MD Anderson Cancer Center
    Nivolumab, Fluorouracil, and Interferon Alpha-2B Clinical Trial
    2021 – 2022

    Goal: Assess the potential of the combination of nivolumab, fluorouracil, and interferon alpha-2b as a treatment option

    Principal Investigators: Sunyoung Lee, MD and Ahmed Kaseb, MD, University of Texas M.D. Anderson Cancer Center

    This phase I/II trial studies the side effects and how well the combination of nivolumab, fluorouracil, and interferon alpha-2b work for the treatment of fibrolamellar carcinoma (FLC) that cannot be removed by surgery. Immunotherapy with checkpoint inhibitors, such as nivolumab, may help the body’s immune system attack the cancer and may interfere with the ability of tumor cells to grow and spread. Treatment with a combination of nivolumab, fluorouracil, and interferon alpha-2b may work better in treating unresectable fibrolamellar cancer compared to treatment with fluorouracil and interferon alpha-2b alone. This clinical trial stages the drug administration and includes the analysis of “before and after” patient biopsies (samples of tumor tissue) to better understand how the drug combination may affect patients’ immune responses to FLC.
  • Johns Hopkins University
    Opening of FLC Peptide Vaccine Clinical Trial
    2020 – 2021

    Goal: Assess potential to induce immune response with a FLC therapeutic vaccine

    Principal Investigator: Mark Yarchoan, MD, Assistant Professor, Oncology/Division of GI Malignancies, Sidney Kimmel Comprehensive Cancer Center

    A new clinical trial of an immune therapy for fibrolamellar carcinoma (FLC) is now recruiting subjects at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, MD. The study investigates whether individuals can mount an effective immune response against FLC by specifically targeting the unique chimeric protein (resulting from a DNAJB1-PRKACA gene fusion) believed to drive the growth of almost all such tumors. Trial subjects will be given an experimental vaccine containing a peptide (small segment of a protein) that corresponds to the junction region linking the two parts of the chimeric protein. They will simultaneously receive two FDA-approved drugs, Opdivo (nivolumab) and Yervoy (ipilimumab), that may enhance the immune response against FLC by overcoming “checkpoint” systems that can limit the immune system’s ability to fight a cancer. Details and contact information can be found at: https://www.clinicaltrials.gov/ct2/show/NCT-04248569
  • Johns Hopkins University
    A Pilot Study of a DNAJB1-PRKACA Fusion Kinase Vaccine Combined with Nivolumab and Ipilimumab for Patients with Fibrolamellar Carcinoma (FLC)
    2019-2021

    Goal: Assess potential to induce immune response with a FLC therapeutic vaccine

    Principal Investigator: Mark Yarchoan, MD, Assistant Professor, Oncology/Division of GI Malignancies, Sidney Kimmel Comprehensive Cancer Center

    FLC is a rare and often lethal form of liver cancer for which there is no standard treatment option beyond surgery. Immune checkpoint inhibitors are a revolutionary new form of cancer therapy. These drugs “take the brakes off” the immune system, enhancing its ability to fight cancer. Examples of these new medicines include the PD1 inhibitor nivolumab (Opdivo), and the CTLA-4 inhibitor ipilimumab (Yervoy). Many patients with FLC currently receive an immune checkpoint inhibitor off-label. However, our clinical experience suggests that they generally do not achieve strong anti-tumor responses from single checkpoint inhibitors. We seek to develop immunotherapy approaches to FLC that offer greater clinical benefit.

    This project entails the first test in patients of a combination of two checkpoint inhibitors (nivolumab and ipilimumab) plus a new vaccine designed to direct the immune response against FLC by targeting the DNAJ-PKAc fusion protein found in almost every case of this cancer. The fusion protein serves as a neoantigen, an abnormal protein found in the cancer but absent from normal cells. The selective component of the vaccine is a peptide (short segment of a protein) overlapping the junction between the DNAJ and PKAc segments of the fusion protein, which is precise and consistent among FLC tumors. Thus, the vaccine could be harnessed by the immune system to recognize and eliminate cancer cells in any FLC patient with the characteristic gene fusion, in contrast to cancers for which a neoantigen vaccine must be personalized for each individual patient.

    The primary goal of the study is to begin assessment of the safety and clinical activity of the FLC-vaccine in combination with nivolumab and ipilimumab in patients for whom complete surgical resection of the cancer is not possible. We also seek to determine if the combination of peptide vaccine and checkpoint inhibitors will promote induction and/or expansion of T cells that specifically recognize the DNAJ-PKAc fusion protein.
  • Memorial Sloan Kettering
    Everolimus Clinical trial
    2012 – 2014

    Goal: Assess potential of treatment options for FLC

    Principal Investigator: Ghassan Abou-Alfa, MD, Memorial Sloan Kettering Cancer Center

    FCF funded the first clinical trial of drugs aimed specifically at fibrolamellar liver cancer.  The trial was also conducted at other consortium members, including the University of California San Francisco, Johns Hopkins, and Dana Farber. Two major pharmaceutical companies donated the drugs.  

    Key findings: Estrogen deprivation therapy with letrozole and leuprolide, alone or in combination with the mTOR inhibitor, everolimus, did not demonstrate clinical activity in advanced fibrolamellar carcinoma.

    Click here to read the published results of the study.

View of participants in the 2019 FCF Scientific Conference