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.
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Research Article Hepatology Oncology

Targeting BCL-XL in fibrolamellar hepatocellular carcinoma

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

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Figure 6

The i.v. formulation of DT2216 synergizes with irinotecan, leading to a sustained complete remission in FLC PDX.

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The i.v. formulation of DT2216 synergizes with irinotecan, leading to a ...
(A) Illustration of treatment timeline for PDX 31. DT2216 was administered i.v. once a week for the entire treatment cycle; an intermediate dose of irinotecan (5 mg/kg) was administered for 2 treatment cycles, 5 days a week. The third week of each treatment cycle, the mice were off irinotecan. (B) Changes in tumor volume over the course of the treatment cycle. Data are presented as the mean ± SEM (n = 4 for vehicle group and n = 5 for the rest of the treatment groups at the start of the treatment for PDX 31). (C) Changes in tumor volume over the entire timeline (treatment cycle + extended monitoring beyond treatment). (D) Tumor images of FLC PDX–engrafted mice after the end of treatment and monitoring at day 47 for vehicle and day 102 for the irinotecan and irinotecan + DT2216 cohorts. ****P < 0.0001 in indicated comparisons. Resistant FLC models exhibit durable clinical benefit to DT2216 and irinotecan. (E) Illustration of treatment timeline for PDX 32. DT2216 was administered i.v. once a week for the entire treatment cycle; an intermediate dose of irinotecan (5 mg/kg) was administered for 2 treatment cycles, 5 days a week. The third week of each treatment cycle, the mice were off irinotecan. (F) Changes in tumor volume over the course of the treatment cycle. Data are presented as the mean ± SEM (n = 5 for vehicle group, n = 6 for the irinotecan treatment group, and n = 7 for the combo treatment group at the start of the treatment for PDX 32). (G) Changes in tumor volume over the entire timeline (treatment cycle + extended monitoring beyond treatment). *P < 0. 05, **P < 0.01, and ****P < 0.0001, as determined by Linear mixed-effects regression model.