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

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 languageEnglish (US)
JournalPediatric Blood and Cancer
DOIs
StateAccepted/In press - 2016

Fingerprint

Heterografts
Pediatrics
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Neoplasms
Inhibitory Concentration 50
Disease-Free Survival
Rhabdoid Tumor
Cell Line
Rhabdomyosarcoma
Osteosarcoma
CBLC137
Neuroblastoma
Pharmaceutical Preparations
Chromatin
Shock
Animal Models
Hot Temperature
Growth

Keywords

  • Curaxin cbl0137
  • Developmental therapeutics
  • Preclinical testing

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Oncology

Cite this

Lock, R., Carol, H., Maris, J. M., Kolb, E. A., Gorlick, R., Reynolds, C. P., ... Smith, M. A. (Accepted/In press). Initial testing (stage 1) of the curaxin CBL0137 by the pediatric preclinical testing program. Pediatric Blood and Cancer. https://doi.org/10.1002/pbc.26263

Initial testing (stage 1) of the curaxin CBL0137 by the pediatric preclinical testing program. / Lock, Richard; Carol, Hernan; Maris, John M.; Kolb, E. Anders; Gorlick, Richard; Reynolds, C. Patrick; Kang, Min H.; Keir, Stephen T.; Wu, Jianrong; Purmal, Andrei; Gudkov, Andrei; Kurmashev, Dias; Kurmasheva, Raushan T.; Houghton, Peter J.; Smith, Malcolm A.

In: Pediatric Blood and Cancer, 2016.

Research output: Contribution to journalArticle

Lock, R, Carol, H, Maris, JM, Kolb, EA, Gorlick, R, Reynolds, CP, Kang, MH, Keir, ST, Wu, J, Purmal, A, Gudkov, A, Kurmashev, D, Kurmasheva, RT, Houghton, PJ & Smith, MA 2016, 'Initial testing (stage 1) of the curaxin CBL0137 by the pediatric preclinical testing program', Pediatric Blood and Cancer. https://doi.org/10.1002/pbc.26263
Lock, Richard ; Carol, Hernan ; Maris, John M. ; Kolb, E. Anders ; Gorlick, Richard ; Reynolds, C. Patrick ; Kang, Min H. ; Keir, Stephen T. ; Wu, Jianrong ; Purmal, Andrei ; Gudkov, Andrei ; Kurmashev, Dias ; Kurmasheva, Raushan T. ; Houghton, Peter J. ; Smith, Malcolm A. / Initial testing (stage 1) of the curaxin CBL0137 by the pediatric preclinical testing program. In: Pediatric Blood and Cancer. 2016.
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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.",
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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.

PY - 2016

Y1 - 2016

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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DO - 10.1002/pbc.26263

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