학술논문
Initial testing (stage 1) of the curaxin CBL0137 by the pediatric preclinical testing program.
Document Type
Academic Journal
Author
Lock R; Children's Cancer Institute Australia for Medical Research, Randwick, New South Wales, Australia.; Carol H; Children's Cancer Institute Australia for Medical Research, Randwick, New South Wales, Australia.; Maris JM; Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine and Abramson Family Cancer Research Institute, Philadelphia, Pennsylvania.; Kolb EA; A.I. duPont Hospital for Children, Wilmington, Delaware.; Gorlick R; The Children's Hospital at Montefiore, Bronx, New York.; Reynolds CP; Texas Tech University Health Sciences Center, Lubbock, Texas.; Kang MH; Texas Tech University Health Sciences Center, Lubbock, Texas.; Keir ST; Duke University Medical Center, Durham, North Carolina.; Wu J; St. Jude Children's Research Hospital, Memphis, Tennessee.; Purmal A; Incuron LLC, Buffalo, New York.; Gudkov A; Roswell Park Cancer Institute, Buffalo, New York.; Kurmashev D; Nationwide Children's Hospital, Columbus, Ohio.; Kurmasheva RT; Nationwide Children's Hospital, Columbus, Ohio.; Houghton PJ; Nationwide Children's Hospital, Columbus, Ohio.; Smith MA; Cancer Therapy Evaluation Program, NCI, Bethesda, Maryland.
Source
Publisher: John Wiley Country of Publication: United States NLM ID: 101186624 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1545-5017 (Electronic) Linking ISSN: 15455009 NLM ISO Abbreviation: Pediatr Blood Cancer Subsets: MEDLINE
Subject
Language
English
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 (rIC 50 ) value for the PPTP cell lines was 0.28 μM (range: 0.13-0.80 μM). There were no significant differences in rIC 50 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.
(© 2016 Wiley Periodicals, Inc.)
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 IC
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.
(© 2016 Wiley Periodicals, Inc.)