Initial testing (stage 1) of the curaxin CBL0137 by the pediatric preclinical testing program

Richard Lock; Hernan Carol; John M. Maris; E. Anders Kolb; Richard Gorlick; C. Patrick Reynolds; Min H. Kang; Stephen T. Keir; Jianrong Wu; Andrei Purmal; Andrei Gudkov; Dias Kurmashev; Raushan T. Kurmasheva; Peter J. Houghton; Malcolm A. Smith

doi:10.1002/pbc.26263

Initial testing (stage 1) of the curaxin CBL0137 by the pediatric preclinical testing program

Richard Lock, Hernan Carol, John M. Maris, E. Anders Kolb, Richard Gorlick, C. Patrick Reynolds, Min H. Kang, Stephen T. Keir, Jianrong Wu, Andrei Purmal, Andrei Gudkov, Dias Kurmashev, Raushan T. Kurmasheva, Peter J. Houghton, Malcolm A. Smith

Internal Medicine

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

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
Article number	e26263
Journal	Pediatric Blood and Cancer
Volume	64
Issue number	4
DOIs	https://doi.org/10.1002/pbc.26263
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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/pbc.26263

Cite this

Lock, R., Carol, H., Maris, J. M., Kolb, E. A., Gorlick, R., Reynolds, C. P., Kang, M. H., Keir, S. T., Wu, J., Purmal, A., Gudkov, A., Kurmashev, D., Kurmasheva, R. T., Houghton, P. J., & Smith, M. A. (2017). Initial testing (stage 1) of the curaxin CBL0137 by the pediatric preclinical testing program. Pediatric Blood and Cancer, 64(4), Article e26263. https://doi.org/10.1002/pbc.26263

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title = "Initial testing (stage 1) of the curaxin CBL0137 by the pediatric preclinical testing program",

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.",

keywords = "curaxin cbl0137, developmental therapeutics, preclinical testing",

author = "Richard Lock and Hernan Carol and Maris, {John M.} and Kolb, {E. Anders} and Richard Gorlick and Reynolds, {C. Patrick} and Kang, {Min H.} and Keir, {Stephen T.} and Jianrong Wu and Andrei Purmal and Andrei Gudkov and Dias Kurmashev and Kurmasheva, {Raushan T.} and Houghton, {Peter J.} and Smith, {Malcolm A.}",

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{\textquoteright}s Cancer Institute Australia for Medical Research is affiliated with the University of New South Wales and the Sydney Children{\textquoteright}s Hospitals Network. Andrei Gudkov was previously the Cleveland BioLabs{\textquoteright} 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: {\textcopyright} 2016 Wiley Periodicals, Inc.",

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T1 - Initial testing (stage 1) of the curaxin CBL0137 by the pediatric preclinical testing program

AU - Lock, Richard

AU - Carol, Hernan

AU - Maris, John M.

AU - Kolb, E. Anders

AU - Gorlick, Richard

AU - Reynolds, C. Patrick

AU - Kang, Min H.

AU - Keir, Stephen T.

AU - Wu, Jianrong

AU - Purmal, Andrei

AU - Gudkov, Andrei

AU - Kurmashev, Dias

AU - Kurmasheva, Raushan T.

AU - Houghton, Peter J.

AU - Smith, Malcolm A.

N1 - 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.

PY - 2017/4/1

Y1 - 2017/4/1

N2 - 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.

AB - 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.

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JO - Pediatric Blood and Cancer

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ER -

Initial testing (stage 1) of the curaxin CBL0137 by the pediatric preclinical testing program

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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