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University of Washington, Seattle, WA
Molecular Therapies for Fibrolamellar Carcinoma (FLC) 2019 – 2021
Principal Investigator: John Scott, PhD, Edwin G. Krebs-Speights Professor of Cell Signaling and Cancer Biology, and Chair, Department of Pharmacology
Successes in precision medicine have identified the underlying genetic defect in FLC as a deletion in chromosome 19. Consequently, FLC patients produce a unique protein where 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 only 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 the 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. The motivation behind this pharmacological approach comes from our conviction that repurposing these drugs will expedite a cure for FLC.
Modulating stromal-immune cell interactions to activate anti-tumor immunity to fibrolamellar carcinoma 2019 -2020 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 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.
Therapeutic Innovations in Fibrolamellar Cancer 2017 – 2019
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 likely affects 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.