Abstract
Background: CBL0137 is a novel drug that modulates FAcilitates Chromatin Transcription (FACT), resulting in simultaneous nuclear factor-κB suppression, heat shock factor 1 suppression and p53 activation. CBL0137 has demonstrated antitumor effects in animal models of several adult cancers and neuroblastoma. Procedures: CBL0137 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro cell line panel at concentrations ranging from 1.0 nM to 10.0 μM and against the PPTP in vivo solid tumor xenograft and acute lymphocytic leukemia (ALL) panels at 50 mg/kg administered intravenously weekly for 4 weeks. Results: The median relative IC50 (rIC50) value for the PPTP cell lines was 0.28 μM (range: 0.13–0.80 μM). There were no significant differences in rIC50 values by histotype. CBL0137 induced significant differences in event-free survival (EFS) distribution compared to control in 10 of 31 (32%) evaluable solid tumor xenografts and in eight of eight (100%) evaluable ALL xenografts. Significance differences in EFS distribution were observed in four of six osteosarcoma lines, three of three rhabdoid tumor lines and two of six rhabdomyosarcoma lines. No objective responses were observed among the solid tumor xenografts. For the ALL panel, one xenograft achieved complete response and four achieved partial response. Conclusions: The most consistent in vivo activity for CBL0137 was observed against ALL xenografts, with some solid tumor xenograft lines showing tumor growth delay. It will be important to relate the drug levels in mice at 50 mg/kg to those in humans at the recommended phase 2 dose.
Original language | English |
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Article number | e26263 |
Journal | Pediatric Blood and Cancer |
Volume | 64 |
Issue number | 4 |
DOIs | |
State | Published - Apr 1 2017 |
Bibliographical note
Funding Information:This work was supported by NO1-CM-42216, CA21765, and CA108786 from the National Cancer Institute and used CBL0137 supplied by Cleveland Biolabs, Inc. In addition to the authors this paper represents work contributed by the following: Sherry Ansher, Jennifer Richmond, Joshua Courtright, Kathryn Evans, Edward Favours, Henry S. Friedman, Danuta Gasinski, Melissa Sammons, Joe Zeidner, Jianrong Wu, Ellen Zhang, and Jian Zhang. Children’s Cancer Institute Australia for Medical Research is affiliated with the University of New South Wales and the Sydney Children’s Hospitals Network. Andrei Gudkov was previously the Cleveland BioLabs’ Chief Scientific Officer and continues to receive compensation from Cleveland Biolabs. Andrei Purmal is an employee of Incuron LLC, which is a joint subsidiary of the Bioprocess Capital Ventures closed-end investment fund and Cleveland BioLabs. The remaining authors consider that there are no actual or perceived conflicts of interest.
Publisher Copyright:
© 2016 Wiley Periodicals, Inc.
Keywords
- curaxin cbl0137
- developmental therapeutics
- preclinical testing
ASJC Scopus subject areas
- Pediatrics, Perinatology, and Child Health
- Hematology
- Oncology