Molecular therapies for fibrolamellar carcinoma (FLC)

Timeframe: 2019 – date 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 …

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Targeting DNAJB1-PRKACA driven signaling dependencies in FLC

Timeframe: 2019 – 2022 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, …

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Disruption of PKA RIα phase separation by the oncogenic fusion protein in FLC

Timeframe: 2021 – 2022 Goal: Elucidate the molecular mechanisms of FLC and identify new pharmacological agents that could lead to new, effective therapeutics Principal Investigator: Jin Zhang, PhD, Vice Chair and Professor of Pharmacology, Department of Pharmacology In recent studies, the investigation team discovered that the presence of the FLC oncogenic fusion protein disrupts a …

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Therapeutic innovations in fibrolamellar cancer

Timeframe: 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 …

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DNAJB1-PKAc-β-catenin-ALCD-dependent activation of cancer genes plays an essential role in fibrolamellar hepatocellular carcinoma

Timeframe: 2020 – 2021 Goal: Document mechanisms driving FLC and test if treatment with inhibitors of b-catenin may be a potential therapeutic approach for FLC Principal Investigator:  Nikolai Timchenko, PhD, Head of Liver Tumor Biology, Liver Tumor Program; Professor, UC Department of Surgery In the course of studies of pediatric liver cancer, we have identified …

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Creating a fibrolamellar cancer dependency map

Timeframe: 2020 – 2023 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. The project has three main goals to identify potential FLC therapeutics: Developing …

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Novel synergistic combination therapy in fibrolamellar carcinoma

Timeframe: 2022 – 2023 Goal: Knock-out gene targets in a mouse model of FLC to identify potentially effective drug combinations for patients with advanced FLC Principal Investigator: Sean Ronnekleiv-Kelly, MD, Surgical Oncology This study will apply an innovative gene-editing based technology (genome-wide CRISPR knockout screen) on a mouse cellular model to screen all possible cancer …

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Identifying therapeutic vulnerabilities in fibrolamellar carcinoma

Timeframe: 2020 – 2023 Goal: Investigate the impact on FLC growth and survival of inhibiting two specific oncogenes identified in previous works Principal Investigator: Praveen Sethupathy Associate Professor Department of Biomedical Sciences, Cornell University, College of Veterinary Medicine Based on previous epigenomic, metabolomic, and microRNA profiling, as well as initial drug studies, the study team …

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Characterization of mitochondria alterations and their functional consequences in fibrolamellar carcinoma (FLC) and FLC-like BAP1 hepatocellular carcinoma

Timeframe: 2022 – 2023 Goal: Identify functional role of mitochondrial alterations in FLC and FLC-Like BAP1 HCC Principal Investigator: Jessica Zucman-Rossi, MD, PhD, Functional Genomics of Solid Tumors Recently, important research studies have reported specific genomic abnormalities of tumor subtypes. One of these, representing the fusion between DNAJB1 and PRKACA genes, has been described to …

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