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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Molecular therapies for fibrolamellar carcinoma (FLC)

Timeframe: 2019 – 2023 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 Study overview: Precision medicine approaches have identified the underlying genetic defect in FLC as a deletion in chromosome 19. Consequently, FLC patients produce a unique protein …

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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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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, PhD Study overview: Based on previous epigenomic, metabolomic, and microRNA profiling, as well as initial drug studies, the study team has developed two new exciting hypotheses about therapeutic vulnerabilities …

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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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