{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:00:43Z","timestamp":1785427243925,"version":"3.56.0"},"reference-count":35,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T00:00:00Z","timestamp":1779840000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FibroFighters Foundation"},{"id":[{"id":"https:\/\/ror.org\/001av7v52","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Fibrolamellar carcinoma (FLC) is a rare liver malignancy affecting adolescents. FLCs harbor a DNAJB1\u2013PRKACA gene fusion that combines heat shock protein DNAJB1 with the catalytic subunit of protein kinase A. Surgery with systemic therapy provides 5-year survivals of 30\u201350%, but advanced disease remains largely incurable. Three-dimensional explants from 41 FLC patients were interrogated for drug sensitivity, resistance, and synergy against cytotoxics, targeted agents, and signal transduction inhibitors. Methods: Sterile specimens from histologically confirmed FLC patients were analyzed by Ex Vivo Analysis of Programmed Cell Death (EVA\/PCD\u2122) in a CLIA-licensed laboratory. Following mechanical and enzymatic disaggregation, explants underwent 72 h drug exposure. LC50 values were derived from five-point dose\u2013response curves and compared with a database of over 10,000 human tumor analyses. Synergy was assessed by combination index. In parallel, targeted metabolomic profiling was performed in five FLC patients using tandem MS\/MS. Results: Forty-one samples were analyzed. Of 24 drugs selected, tumor-cell yields were adequate for testing in 18 (75%). Single-agent activity favored vorinostat, followed by phenformin and 6-diazo-5-oxo-L-norleucine. Combinations favored gemcitabine plus oxaliplatin (GEMOX) and 5-FU plus interferon. Metabolomic analysis identified distinct signature consistent with mitochondrial dysfunction and altered polyamine metabolism. Conclusions: The present findings are exploratory, and hypothesis-generating and should not be interpreted as evidence of clinical efficacy. Prospective clinical validation and mechanistic studies will be required to further define the therapeutic relevance of these observations in fibrolamellar carcinoma.<\/jats:p>","DOI":"10.3390\/cancers18111744","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T11:03:27Z","timestamp":1779879807000},"page":"1744","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Functional Precision Oncology in Fibrolamellar Carcinoma: Ex Vivo Identification of Therapeutic Vulnerabilities"],"prefix":"10.3390","volume":"18","author":[{"given":"Sabina A.","family":"Schneider","sequence":"first","affiliation":[{"name":"Nagourney Cancer Institute, 750 East 29th Street, Long Beach, CA 90806, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2341-5340","authenticated-orcid":false,"given":"Paulo","family":"D\u2019Amora","sequence":"additional","affiliation":[{"name":"Nagourney Cancer Institute, 750 East 29th Street, Long Beach, CA 90806, USA"},{"name":"Metabolomycs, Inc., 750 East 29th Street, Long Beach, CA 90806, USA"},{"name":"Gynecology Department, School of Medicine of the Federal University of S\u00e3o Paulo (EPM-UNIFESP), Rua Pedro de Toledo 781, S\u00e3o Paulo 04039-032, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven S.","family":"Evans","sequence":"additional","affiliation":[{"name":"Nagourney Cancer Institute, 750 East 29th Street, Long Beach, CA 90806, USA"},{"name":"Metabolomycs, Inc., 750 East 29th Street, Long Beach, CA 90806, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5893-0313","authenticated-orcid":false,"given":"Paul","family":"Kent","sequence":"additional","affiliation":[{"name":"FibroFighters Foundation, 31805 Temecula Parkway #D7-512, Temecula, CA 92592, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Stockwell","sequence":"additional","affiliation":[{"name":"FibroFighters Foundation, 31805 Temecula Parkway #D7-512, Temecula, CA 92592, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikrant S.","family":"Bakaya","sequence":"additional","affiliation":[{"name":"Nagourney Cancer Institute, 750 East 29th Street, Long Beach, CA 90806, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula J.","family":"Bernard","sequence":"additional","affiliation":[{"name":"Nagourney Cancer Institute, 750 East 29th Street, Long Beach, CA 90806, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico R.","family":"Francisco","sequence":"additional","affiliation":[{"name":"Nagourney Cancer Institute, 750 East 29th Street, Long Beach, CA 90806, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"Torres","sequence":"additional","affiliation":[{"name":"Nagourney Cancer Institute, 750 East 29th Street, Long Beach, CA 90806, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"John","family":"Henry","sequence":"additional","affiliation":[{"name":"Nagourney Cancer Institute, 750 East 29th Street, Long Beach, CA 90806, USA"},{"name":"Metabolomycs, Inc., 750 East 29th Street, Long Beach, CA 90806, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ismael D. C. G.","family":"Silva","sequence":"additional","affiliation":[{"name":"Gynecology Department, School of Medicine of the Federal University of S\u00e3o Paulo (EPM-UNIFESP), Rua Pedro de Toledo 781, S\u00e3o Paulo 04039-032, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Nagourney","sequence":"additional","affiliation":[{"name":"Nagourney Cancer Institute, 750 East 29th Street, Long Beach, CA 90806, USA"},{"name":"Metabolomycs, Inc., 750 East 29th Street, Long Beach, CA 90806, USA"},{"name":"Department of Obstetrics and Gynecology, University of California Irvine (UC Irvine), 101 The City Drive South, Orange, CA 92868, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.jamcollsurg.2013.10.011","article-title":"Treatment and Prognosis of Patients with Fibrolamellar Hepatocellular Carcinoma: A National Perspective","volume":"218","author":"Mayo","year":"2014","journal-title":"J. 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