Identification of novel therapeutic targets for fibrolamellar carcinoma using patient-derived xenografts and direct-from-patient screening Journal Article
| Authors: | Lalazar, G.; Requena, D.; Ramos-Espiritu, L.; Ng, D.; Bhola, P. D.; de Jong, Y. P.; Wang, R.; Narayan, N. J. C.; Shebl, B.; Levin, S.; Michailidis, E.; Kabbani, M.; Vercauteren, K. O. A.; Hurley, A. M.; Farber, B. A.; Hammond, W. J.; Saltsman, J. A. 3rd; Weinberg, E. M.; Glickman, J. F.; Lyons, B. A.; Ellison, J.; Schadde, E.; Hertl, M.; Leiting, J. L.; Truty, M. J.; Smoot, R. L.; Tierney, F.; Kato, T.; Wendel, H. G.; LaQuaglia, M. P.; Rice, C. M.; Letai, A.; Coffino, P.; Torbenson, M. S.; Ortiz, M. V.; Simon, S. M. |
| Article Title: | Identification of novel therapeutic targets for fibrolamellar carcinoma using patient-derived xenografts and direct-from-patient screening |
| Abstract: | To repurpose therapeutics for fibrolamellar carcinoma (FLC), we developed and validated patient-derived xenografts (PDX) from surgical resections. Most agents used clinically and inhibitors of oncogenes overexpressed in FLC showed little efficacy on PDX. A highthroughput functional drug screen found primary and metastatic FLC were vulnerable to clinically available inhibitors of TOPO1 and HDAC and to napabucasin. Napabucasin’s efficacy was mediated through reactive oxygen species and inhibition of translation initiation, and specific inhibition of eIF4A was effective. The sensitivity of each PDX line inversely correlated with expression of the antiapoptotic protein Bcl-xL, and inhibition of Bcl-xL synergized with other drugs. Screening directly on cells dissociated from patient resections validated these results. This demonstrates that a direct functional screen on patient tumors provides therapeutically informative data within a clinically useful time frame. Identifying these novel therapeutic targets and combination therapies is an urgent need, as effective therapeutics for FLC are currently unavailable. SIGNIFICANCE: Therapeutics informed by genomics have not yielded effective therapies for FLC. A functional screen identified TOPO1, HDAC inhibitors, and napabucasin as efficacious and synergistic with inhibition of Bcl-xL. Validation on cells dissociated directly from patient tumors demonstrates the ability for functional precision medicine in a solid tumor. © 2021 The Authors; Published by the American As sociation for Cancer Research. |
| Keywords: | immunohistochemistry; adolescent; adult; controlled study; human tissue; protein expression; unclassified drug; histone deacetylase inhibitor; histopathology; sorafenib; drug efficacy; nonhuman; topotecan; ki 67 antigen; mouse; animal tissue; cell viability; protein bcl 2; stat3 protein; reverse transcription polymerase chain reaction; proteasome inhibitor; mitogen activated protein kinase inhibitor; animal experiment; animal model; aromatase inhibitor; cancer screening; antineoplastic activity; high throughput screening; tumor xenograft; protein bcl xl; histology; irinotecan; protein tyrosine kinase inhibitor; albumin; luminescence; protein synthesis; histone h3; myc protein; protein mcl 1; western blotting; staining; immunoblotting; reactive oxygen metabolite; eosin; hematoxylin; idarubicin; drug cytotoxicity; mammalian target of rapamycin inhibitor; cyclin d1; oxidoreductase; initiation factor 4a; drug sensitivity; transcriptome; obatoclax; panobinostat; spectroscopy; histone deacetylase; epidermal growth factor receptor kinase inhibitor; drug formulation; neratinib; dna topoisomerase; protein isolation; cyclic amp dependent protein kinase; fusion protein; isoflurane; rna isolation; thioredoxin; amoxicillin; buprenorphine; navitoclax; transcription factor nrf2; synergistic effect; epigenetic modification; protein dnaj; quisinostat; human; male; female; article; fibrolamellar hepatocellular carcinoma; rna sequencing; drug repositioning; ryuvidine; ic50; uprosertib; venetoclax; firtecan; ec50; tunel assay; vlx 1570; dinaciclib; jib 04; cytochrome p450 reductase; fimepinostat; napabucasin; capivasertib; mouse double minute 2 homolog; 8 (6 methoxy 3 pyridinyl) 3 methyl 1 [4 (1 piperazinyl) 3 (trifluoromethyl)phenyl] 1h imidazo[4,5 c]quinolin 2(3h) one; alvocidib; at13148; carbonyl reductase 1; cr 1 31 b; cyclic amp dependent protein kinase inhibitor; dnaj subfamily b member 1; enmd 2076; frax597; kt 5720; nms873; nsc697923; p5091; pik 75; protein kinase cyclic amp activated catalytic subunit alpha; reduced nicotinamide adenine dinucleotide (phosphate) dehydrogenase (quinone) 1 |
| Journal Title: | Cancer Discovery |
| Volume: | 11 |
| Issue: | 10 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2021-10-01 |
| Start Page: | 2544 |
| End Page: | 2563 |
| Language: | English |
| DOI: | 10.1158/2159-8290.Cd-20-0872 |
| PROVIDER: | scopus |
| PUBMED: | 34127480 |
| PMCID: | PMC8734228 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 December 2021 -- Source: Scopus |
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