2. Academic Validation
  3. Identification of Novel Therapeutic Targets for Fibrolamellar Carcinoma Using Patient-Derived Xenografts and Direct-from-Patient Screening

Identification of Novel Therapeutic Targets for Fibrolamellar Carcinoma Using Patient-Derived Xenografts and Direct-from-Patient Screening

  • Cancer Discov. 2021 Oct;11(10):2544-2563. doi: 10.1158/2159-8290.CD-20-0872.
Gadi Lalazar 1 2,  David Requena 1,  Lavoisier Ramos-Espiritu 3,  Denise Ng 1,  Patrick D Bhola 4,  Ype P de Jong 2 5,  Ruisi Wang 1,  Nicole J C Narayan 1 6,  Bassem Shebl 1,  Solomon Levin 1,  Eleftherios Michailidis 5,  Mohammad Kabbani 5,  Koen O A Vercauteren 5 7 8,  Arlene M Hurley 9,  Benjamin A Farber 1 10,  William J Hammond 1 6 11,  James A Saltsman 3rd 1 6 12,  Ethan M Weinberg 13,  J Fraser Glickman 3,  Barbara A Lyons 14,  Jessica Ellison 15,  Erik Schadde 16,  Martin Hertl 15,  Jennifer L Leiting 17,  Mark J Truty 17,  Rory L Smoot 17,  Faith Tierney 18,  Tomoaki Kato 18,  Hans-Guido Wendel 19,  Michael P LaQuaglia 6,  Charles M Rice 5,  Anthony Letai 4,  Philip Coffino 1,  Michael S Torbenson 20,  Michael V Ortiz 21,  Sanford M Simon 22
Affiliations

Affiliations

  • 1 Laboratory of Cellular Biophysics, The Rockefeller University, New York, New York.
  • 2 Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, New York.
  • 3 High Throughput and Spectroscopy Resource Center, The Rockefeller University, New York, New York.
  • 4 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 5 Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York.
  • 6 Pediatric Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 7 Laboratory of Liver Infectious Diseases, Ghent University, Ghent, Belgium.
  • 8 Institute of Tropical Medicine, Antwerp, Belgium.
  • 9 Hospital Program Direction, The Rockefeller University, New York, New York.
  • 10 Department of Surgery, Division of Pediatric Surgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa.
  • 11 Department of Surgery, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, New York.
  • 12 Department of Surgery, Mount Sinai Hospital, New York, New York.
  • 13 Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 14 Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, New Mexico.
  • 15 Division of Transplantation, Rush University Medical Center, Chicago, Illinois.
  • 16 Department of Surgery, Division of Transplantation and Division of Surgical Oncology, Rush University Medical Center, Chicago, Illinois.
  • 17 Division of Subspecialty General Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota.
  • 18 Division of Abdominal Organ Transplantation, New York-Presbyterian/Columbia University, New York, New York.
  • 19 Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 20 Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota.
  • 21 Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 22 Laboratory of Cellular Biophysics, The Rockefeller University, New York, New York. simon@rockefeller.edu.
PMID: 34127480 DOI: 10.1158/2159-8290.CD-20-0872
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 high-throughput 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.This article is highlighted in the In This Issue feature, p. 2355.

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