Molecular therapies for fibrolamellar carcinoma (FLC) – continuation

Timeframe: 2023 – 2025 Goal: Investigate alternate means of therapeutically targeting DNAJ-PKAc Principal Investigator: John Scott, PhD Study overview: Previous work has established that the fusion protein interacts with large number of binding partners as compared to the native protein by increased association with the AKAP proteins (the latter acts as a scaffold). One of …

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Retinoic acid-induced loss of DNAJB1-PRKACA fusion protein expression

Timeframe: 2019 – 2023 Goal: Investigate the potential of retinoic acid therapy Principal Investigators: Andrew Yen, PhD and Praveen Sethupathy, PhD Study overview: 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 …

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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 Study overview: 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 be typical of …

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

Timeframe: 2021 – 2023 Goals: Determine the molecular mechanisms of FLC and identify new pharmacological agents that could lead to effective therapeutics Principal Investigator: Jin Zhang, PhD Study overview: In recent studies, the investigation team discovered that the presence of the FLC oncogenic fusion protein disrupts a membraneless organelle. They showed that loss of this …

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Development and Characterization of Patient-derived Models of Fibrolamellar Carcinoma

Timeframe: 2023 – 2025 Goal: Evaluate selective inhibitors of polo-like kinase 1 (PLK1) for effectiveness in human models of FLC Principal Investigator: Taran Gujral, PhD Study overview: Abormal cell signaling by the DNAJ-PKAc fusion protein kinase drives the uncontrolled growth of fibrolamellar carcinoma. Thus far, however, drugs that inhibit the fusion kinase also block the …

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Elucidation of nuclear-mitochondrial signaling by DNAJ-PKAc to define targeted vulnerabilities in FLC

Timeframe: 2022 – 2025 Goals: Identifying how the DNAJ-PKAc/SIK/p300 program controls mitochondrial function and define how these abnormal mitochondria affect the metabolism of FLC cells Principal Investigator: Nabeel M. Bardeesy, PhD Study overview: Signals that control the growth and metabolism of cells often are relayed through a series of reactions in which proteins are sequentially …

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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 Study overview: 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: If fully successful, this effort will nominate high priority …

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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 Study overview: 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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