Fibrolamellar carcinoma (FLC), a rare, lethal hepatic cancer, occurs primarily in adolescents and young adults. Unlike hepatocellular carcinoma, FLC has no known association with viral, metabolic or chemical agents that cause cirrhosis. Currently, surgical resection is the only treatment demonstrated to achieve cure, and no standard of care exists for systemic therapy. Progress in FLC research illuminates a transition from an obscure cancer to one for which an interactive community seems poised to uncover fundamental mechanisms and initiate translation towards novel therapies. In this Roadmap, we review advances since the seminal discovery in 2014 that nearly all FLC tumours express a signature oncogene (DNAJB1–PRKACA) encoding a fusion protein (DNAJ–PKAc) in which the J-domain of a heat shock protein 40 (HSP40) co-chaperone replaces an amino-terminal segment of the catalytic subunit of the cyclic AMP-dependent protein kinase (PKA). Important gains include increased understanding of oncogenic pathways driven by DNAJ–PKAc; identification of potential therapeutic targets; development of research models; elucidation of immune mechanisms with potential for the development of immunotherapies; and completion of the first multicentre clinical trials of targeted therapy for FLC. In each of these key areas we propose a Roadmap for future progress.
Fibrolamellar carcinoma (FLC) is a rare but devastating disease that disproportionately affects adolescents and young adults and is characterized by the fusion oncogene DNAJB1–PRKACA.
There is a critical need to establish new cellular and animal models of FLC to perform reliable functional and preclinical studies.
Efforts to directly inhibit cyclic AMP-dependent protein kinase (PKA) catalytic activity for FLC therapy might be constrained by the important role of the normal enzyme in multiple tissues; a deeper understanding of mechanisms underlying cellular transformation by the oncogenic chimaera remains essential to defining tractable pharmacological targets.
Advances in the genetic and molecular underpinnings of FLC, in part through the application of genome-scale techniques, reveal promising avenues for new targeted therapeutic strategies and motivate higher-resolution single-cell and spatial approaches.
Immunotherapy for FLC must overcome the challenge of generating responses against a low-tumour mutational burden cancer, potentially by targeting the specific fusion oncoprotein as a neoantigen.
Clinical trials must overcome obstacles to accruing sufficient patients and should utilize an evidence-based approach and collaborative networks tailored to rare cancers.
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The oncogenic fusion protein DNAJB1-PRKACA can be specifically targeted by peptide-based immunotherapy in fibrolamellar hepatocellular carcinoma
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The authors thank participants at the 2019 Fibrolamellar Research Summit (funded and hosted by the Fibrolamellar Cancer Foundation) and many other members of the FLC research and patient/caregiver communities for their insightful contributions. The authors thank M. Torbenson for providing the histology micrograph in Fig. 1.
E.M.J. is a paid consultant for the following companies: Adaptive Biotech, Cstone Pharmaceuticals, Achilles Therapeutics, DragonFly Therapeutics, Candel Therapeutics and Genocea Biosciences. She receives funding from Lustgarten Foundation and Bristol Myers Squibb. She is the Chief Medical Advisor for Lustgarten and SAB advisor to the Parker Institute for Cancer Immunotherapy (PICI) and for the C3 Cancer Institute. She is a founding member of Abmeta. G.K.A.-A. has had research support from Arcus, Agios, AstraZeneca, Bayer, BioNtech, BMS, Celgene, Flatiron, Genentech/Roche, Genoscience, Incyte, Polaris, Puma, QED, Sillajen, and Yiviva. He has also provided consulting to Agios, AstraZeneca, Alnylam, Autem, Bayer, Beigene, Berry Genomics, Celgene, CytomX, Eisai, Eli Lilly, Exelixis, Flatiron, Genentech/Roche, Genoscience, Helio, Incyte, Ipsen, Legend Biotech, Loxo, Merck, MINA, QED, Redhill, Rafael, Silenseed, Sillajen, Sobi, Surface Oncology, Therabionics, Twoxar, Vector and Yiviva. M.E.F. is employed full-time by the Fibrolamellar Cancer Foundation, a registered non-profit corporation (501c3) in the USA. The following authors serve on the advisory board of the Fibrolamellar Cancer Foundation: E.M.J., J.D.S., J.D.G., G.K.A.-A., A.F.O'N. and J.Z.-R. The following authors are past or current recipients of grant funding from the Fibrolamellar Cancer Foundation: J.D.S., J.D.G., G.K.A.-A., K.C.B. and P.S. T.A.D., A.F.U. and R.M. declare no competing interests.
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Cancer Dependency Map: https://depmap.org/portal
European Union Drug Regulating Authorities Clinical Trials Database (EudraCT): https://eudract.ema.europa.eu/
Fibrolamellar Cancer Foundation Biobank: https://fibrofoundation.org/join-the-fight/donate-tissue/
FibroLamellar Omics (FLO): https://sethupathy-lab.shinyapps.io/flc_data/
Fibrolamellar Registry: https://fibroregistry.org/
Fibrolamellar Tissue Repository: https://fibrolamellar.rockefeller.edu/repository
Kinase Chemogenomic Set (KCGS): https://www.sgc-unc.org/kinase-chemogenomics
Natural History Study of Rare Solid Tumors: https://www.cancer.gov/pediatric-adult-rare-tumor/participate/natural-history
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Dinh, T.A., Utria, A.F., Barry, K.C. et al. A framework for fibrolamellar carcinoma research and clinical trials. Nat Rev Gastroenterol Hepatol 19, 328–342 (2022). https://doi.org/10.1038/s41575-022-00580-3
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