Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Targeting BCL-XL in fibrolamellar hepatocellular carcinoma
Bassem Shebl, … , Daohong Zhou, Sanford M. Simon
Bassem Shebl, … , Daohong Zhou, Sanford M. Simon
Published September 8, 2022
Citation Information: JCI Insight. 2022;7(17):e161820. https://doi.org/10.1172/jci.insight.161820.
View: Text | PDF
Research Article Hepatology Oncology

Targeting BCL-XL in fibrolamellar hepatocellular carcinoma

  • Text
  • PDF
Abstract

Fibrolamellar hepatocellular carcinoma (FLC) is a rare and often lethal liver cancer with no proven effective systemic therapy. Inhibition of the antiapoptotic protein BCL-XL was found to synergize with a variety of systemic therapies in vitro using cells dissociated from patient-derived xenografts (PDX) of FLC or cells dissociated directly from surgical patient resections. As BCL-XL is physiologically expressed in platelets, prior efforts to leverage this vulnerability in other cancers have been hampered by severe thrombocytopenia. To overcome this toxicity, we treated FLC models with DT2216, a proteolysis targeting chimera (PROTAC) that directs BCL-XL for degradation via the von Hippel-Lindau (VHL) E3 ligase, which is minimally expressed in platelets. The combination of irinotecan and DT2216 in vitro on cells directly acquired from patients or in vivo using several xenografts derived from patients with FLC demonstrated remarkable synergy and at clinically achievable doses not associated with significant thrombocytopenia.

Authors

Bassem Shebl, Denise Ng, Gadi Lalazar, Carly Rosemore, Tova M. Finkelstein, Rachael D. Migler, Guangrong Zheng, Peiyi Zhang, Caroline S. Jiang, Adam Qureshi, Roger Vaughan, Mark Yarchoan, Ype P. de Jong, Charles M. Rice, Philip Coffino, Michael V. Ortiz, Daohong Zhou, Sanford M. Simon

×

Figure 1

Direct-from-patient screening (DPS) of SN38.

Options: View larger image (or click on image) Download as PowerPoint
Direct-from-patient screening (DPS) of SN38.
(A) Dose-response curves of...
(A) Dose-response curves of SN38 (TOPO1 inhibitor) against 11 patient samples (samples 101–111) and PHH. Cells were treated at 10 μM–10 nM with 2-fold serial dilution. The y axis shows normalized percentage survival calculated as ([positive control – drug response at a given dose]/[positive control – negative control]) × 100. The x axis shows the concentration in μM. Data are presented as mean ± SD (n = 3). (B) Dose-response curves of SN38 in the presence of increasing concentrations of navitoclax. Synergy screening was done on patient sample DPS 102. (C) Comparison of synergy models for SN38-navitoclax combo from B. NPS, normalized percentage survival.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts