Initial testing of the MDM2 inhibitor RG7112 by the pediatric preclinical testing program

Hernan Carol, C. Patrick Reynolds, Min H. Kang, Stephen T. Keir, John M. Maris, Richard Gorlick, E. Anders Kolb, Catherine A. Billups, Brian Geier, Raushan T. Kurmasheva, Peter J. Houghton, Malcolm A. Smith, Richard B. Lock

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Background: RG7112 is a selective inhibitor of p53-MDM2 binding that frees p53 from negative control, activating the p53 pathway in cancer cells leading to cell cycle arrest and apoptosis. RG7112 was selected for evaluation by the Pediatric Preclinical Testing Program (PPTP) due to the relatively low incidence of p53 mutations in pediatric cancers compared with adult malignancies. Procedures: RG7112 and its inactive enantiomer RG7112i were evaluated against the 23 cell lines of the PPTP in vitro panel using 96hours exposure (1nM to 10μM). It was tested against the PPTP in vivo panel focusing on p53 wild-type (WT) xenografts at a dose of 100mg/kg daily for 14 days followed by 4 weeks of observation. Response outcomes were related to MDM2 and p53 expression datasets (http://pptp.nchresearch.org/data.html). Results: RG7112 demonstrated cytotoxic activity with a lower median IC50 for p53 WT versus p53 mutant cell lines (approximately 0.4μM vs >10μM, respectively). RG7112 induced tumor growth inhibition meeting criteria for intermediate activity (EFS T/C>2) in 10 of 26 (38%) solid tumor xenografts. Objective responses included medulloblastoma, alveolar rhabdomyosarcoma, Wilms, rhabdoid and Ewing sarcoma xenografts. For the ALL panel, there was one partial response, five complete responses and one maintained complete response. The ALL xenografts expressed the highest levels of p53 among the PPTP panels. Conclusions: RG7112 induced tumor regressions in solid tumors from different histotype panels, and exhibited consistent high-level activity against ALL xenografts. This high level of activity supports prioritization of RG7112 for further evaluation.

Original languageEnglish (US)
Pages (from-to)633-641
Number of pages9
JournalPediatric Blood and Cancer
Volume60
Issue number4
DOIs
StatePublished - Apr 2013

Fingerprint

Heterografts
Pediatrics
Neoplasms
Alveolar Rhabdomyosarcoma
Cell Line
Medulloblastoma
Ewing's Sarcoma
Cell Cycle Checkpoints
RG7112
Inhibitory Concentration 50
Observation
Apoptosis
Mutation
Incidence
Growth

Keywords

  • Developmental therapeutics
  • Preclinical testing
  • RG7112

ASJC Scopus subject areas

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

Cite this

Carol, H., Reynolds, C. P., Kang, M. H., Keir, S. T., Maris, J. M., Gorlick, R., ... Lock, R. B. (2013). Initial testing of the MDM2 inhibitor RG7112 by the pediatric preclinical testing program. Pediatric Blood and Cancer, 60(4), 633-641. https://doi.org/10.1002/pbc.24235

Initial testing of the MDM2 inhibitor RG7112 by the pediatric preclinical testing program. / Carol, Hernan; Reynolds, C. Patrick; Kang, Min H.; Keir, Stephen T.; Maris, John M.; Gorlick, Richard; Kolb, E. Anders; Billups, Catherine A.; Geier, Brian; Kurmasheva, Raushan T.; Houghton, Peter J.; Smith, Malcolm A.; Lock, Richard B.

In: Pediatric Blood and Cancer, Vol. 60, No. 4, 04.2013, p. 633-641.

Research output: Contribution to journalArticle

Carol, H, Reynolds, CP, Kang, MH, Keir, ST, Maris, JM, Gorlick, R, Kolb, EA, Billups, CA, Geier, B, Kurmasheva, RT, Houghton, PJ, Smith, MA & Lock, RB 2013, 'Initial testing of the MDM2 inhibitor RG7112 by the pediatric preclinical testing program', Pediatric Blood and Cancer, vol. 60, no. 4, pp. 633-641. https://doi.org/10.1002/pbc.24235
Carol, Hernan ; Reynolds, C. Patrick ; Kang, Min H. ; Keir, Stephen T. ; Maris, John M. ; Gorlick, Richard ; Kolb, E. Anders ; Billups, Catherine A. ; Geier, Brian ; Kurmasheva, Raushan T. ; Houghton, Peter J. ; Smith, Malcolm A. ; Lock, Richard B. / Initial testing of the MDM2 inhibitor RG7112 by the pediatric preclinical testing program. In: Pediatric Blood and Cancer. 2013 ; Vol. 60, No. 4. pp. 633-641.
@article{01b7260e43f548558c7e8250318d572c,
title = "Initial testing of the MDM2 inhibitor RG7112 by the pediatric preclinical testing program",
abstract = "Background: RG7112 is a selective inhibitor of p53-MDM2 binding that frees p53 from negative control, activating the p53 pathway in cancer cells leading to cell cycle arrest and apoptosis. RG7112 was selected for evaluation by the Pediatric Preclinical Testing Program (PPTP) due to the relatively low incidence of p53 mutations in pediatric cancers compared with adult malignancies. Procedures: RG7112 and its inactive enantiomer RG7112i were evaluated against the 23 cell lines of the PPTP in vitro panel using 96hours exposure (1nM to 10μM). It was tested against the PPTP in vivo panel focusing on p53 wild-type (WT) xenografts at a dose of 100mg/kg daily for 14 days followed by 4 weeks of observation. Response outcomes were related to MDM2 and p53 expression datasets (http://pptp.nchresearch.org/data.html). Results: RG7112 demonstrated cytotoxic activity with a lower median IC50 for p53 WT versus p53 mutant cell lines (approximately 0.4μM vs >10μM, respectively). RG7112 induced tumor growth inhibition meeting criteria for intermediate activity (EFS T/C>2) in 10 of 26 (38{\%}) solid tumor xenografts. Objective responses included medulloblastoma, alveolar rhabdomyosarcoma, Wilms, rhabdoid and Ewing sarcoma xenografts. For the ALL panel, there was one partial response, five complete responses and one maintained complete response. The ALL xenografts expressed the highest levels of p53 among the PPTP panels. Conclusions: RG7112 induced tumor regressions in solid tumors from different histotype panels, and exhibited consistent high-level activity against ALL xenografts. This high level of activity supports prioritization of RG7112 for further evaluation.",
keywords = "Developmental therapeutics, Preclinical testing, RG7112",
author = "Hernan Carol and Reynolds, {C. Patrick} and Kang, {Min H.} and Keir, {Stephen T.} and Maris, {John M.} and Richard Gorlick and Kolb, {E. Anders} and Billups, {Catherine A.} and Brian Geier and Kurmasheva, {Raushan T.} and Houghton, {Peter J.} and Smith, {Malcolm A.} and Lock, {Richard B.}",
year = "2013",
month = "4",
doi = "10.1002/pbc.24235",
language = "English (US)",
volume = "60",
pages = "633--641",
journal = "Pediatric Blood and Cancer",
issn = "1545-5009",
publisher = "Wiley-Liss Inc.",
number = "4",

}

TY - JOUR

T1 - Initial testing of the MDM2 inhibitor RG7112 by the pediatric preclinical testing program

AU - Carol, Hernan

AU - Reynolds, C. Patrick

AU - Kang, Min H.

AU - Keir, Stephen T.

AU - Maris, John M.

AU - Gorlick, Richard

AU - Kolb, E. Anders

AU - Billups, Catherine A.

AU - Geier, Brian

AU - Kurmasheva, Raushan T.

AU - Houghton, Peter J.

AU - Smith, Malcolm A.

AU - Lock, Richard B.

PY - 2013/4

Y1 - 2013/4

N2 - Background: RG7112 is a selective inhibitor of p53-MDM2 binding that frees p53 from negative control, activating the p53 pathway in cancer cells leading to cell cycle arrest and apoptosis. RG7112 was selected for evaluation by the Pediatric Preclinical Testing Program (PPTP) due to the relatively low incidence of p53 mutations in pediatric cancers compared with adult malignancies. Procedures: RG7112 and its inactive enantiomer RG7112i were evaluated against the 23 cell lines of the PPTP in vitro panel using 96hours exposure (1nM to 10μM). It was tested against the PPTP in vivo panel focusing on p53 wild-type (WT) xenografts at a dose of 100mg/kg daily for 14 days followed by 4 weeks of observation. Response outcomes were related to MDM2 and p53 expression datasets (http://pptp.nchresearch.org/data.html). Results: RG7112 demonstrated cytotoxic activity with a lower median IC50 for p53 WT versus p53 mutant cell lines (approximately 0.4μM vs >10μM, respectively). RG7112 induced tumor growth inhibition meeting criteria for intermediate activity (EFS T/C>2) in 10 of 26 (38%) solid tumor xenografts. Objective responses included medulloblastoma, alveolar rhabdomyosarcoma, Wilms, rhabdoid and Ewing sarcoma xenografts. For the ALL panel, there was one partial response, five complete responses and one maintained complete response. The ALL xenografts expressed the highest levels of p53 among the PPTP panels. Conclusions: RG7112 induced tumor regressions in solid tumors from different histotype panels, and exhibited consistent high-level activity against ALL xenografts. This high level of activity supports prioritization of RG7112 for further evaluation.

AB - Background: RG7112 is a selective inhibitor of p53-MDM2 binding that frees p53 from negative control, activating the p53 pathway in cancer cells leading to cell cycle arrest and apoptosis. RG7112 was selected for evaluation by the Pediatric Preclinical Testing Program (PPTP) due to the relatively low incidence of p53 mutations in pediatric cancers compared with adult malignancies. Procedures: RG7112 and its inactive enantiomer RG7112i were evaluated against the 23 cell lines of the PPTP in vitro panel using 96hours exposure (1nM to 10μM). It was tested against the PPTP in vivo panel focusing on p53 wild-type (WT) xenografts at a dose of 100mg/kg daily for 14 days followed by 4 weeks of observation. Response outcomes were related to MDM2 and p53 expression datasets (http://pptp.nchresearch.org/data.html). Results: RG7112 demonstrated cytotoxic activity with a lower median IC50 for p53 WT versus p53 mutant cell lines (approximately 0.4μM vs >10μM, respectively). RG7112 induced tumor growth inhibition meeting criteria for intermediate activity (EFS T/C>2) in 10 of 26 (38%) solid tumor xenografts. Objective responses included medulloblastoma, alveolar rhabdomyosarcoma, Wilms, rhabdoid and Ewing sarcoma xenografts. For the ALL panel, there was one partial response, five complete responses and one maintained complete response. The ALL xenografts expressed the highest levels of p53 among the PPTP panels. Conclusions: RG7112 induced tumor regressions in solid tumors from different histotype panels, and exhibited consistent high-level activity against ALL xenografts. This high level of activity supports prioritization of RG7112 for further evaluation.

KW - Developmental therapeutics

KW - Preclinical testing

KW - RG7112

UR - http://www.scopus.com/inward/record.url?scp=84873710768&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84873710768&partnerID=8YFLogxK

U2 - 10.1002/pbc.24235

DO - 10.1002/pbc.24235

M3 - Article

VL - 60

SP - 633

EP - 641

JO - Pediatric Blood and Cancer

JF - Pediatric Blood and Cancer

SN - 1545-5009

IS - 4

ER -