Initial testing (stage 1) of the mTOR inhibitor rapamycin by the pediatric preclinical testing program

Peter J. Houghton, Christopher L. Morton, E. Anders Kolb, Richard Gorlick, Richard Lock, Hernan Carol, C. Patrick Reynolds, John M. Maris, Stephen T. Keir, Catherine A. Billups, Malcolm A. Smith

Research output: Contribution to journalArticle

121 Citations (Scopus)

Abstract

Background. Rapamycin is a highly specific inhibitor of mTOR, a serine/threonine kinase that controls cap-dependent translation. Here we report the activity of rapamycin against the in vitro and in vivo panels of the Pediatric Preclinical Testing Program (PPTP). Procedures. Rapamycin was tested against the in vitro panel at concentrations from 0.01 to 100 nM and was tested against the in vivo tumor panels by i.p. administration daily x 5 for 6 consecutive weeks at a dose of 5 mg/kg. Results. Rapamycin variably inhibited growth of the cell lines in the PPTP in vitro panel, with maximal inhibition values ranging from 19% to 85% (median 49%) and a median EC50 of 0.7 nM. Ten of 23 cell lines achieved at least 50% growth inhibition. Against the in vivo panels, rapamycin induced significant differences in EFS distribution in 27 of 36 solid tumor xenografts and in 5 of 8 ALL xenografts. Using the time to event activity measure, rapamycin had intermediate or high activity against 14 of 31 evaluable solid tumor xenografts and 5 of 8 ALL xenografts. Objective responses were observed in several panels, including: rhabdoid tumor (IPR), rhabdomyosarcoma (2PR), and osteosarcoma (1 maintained CR). Two T-cell ALL xenografts had objective responses (1PR, 1 maintained CR). Conclusions. Rapamycin demonstrated broad antitumor activity against the PPTP's in vivo tumor panels, with particularly noteworthy activity for selected sarcoma and ALL xenografts. Future work will evaluate the molecular characteristics of responding models and the activity of combinations of rapamycin with other anticancer agents.

Original languageEnglish (US)
Pages (from-to)799-805
Number of pages7
JournalPediatric Blood and Cancer
Volume50
Issue number4
DOIs
StatePublished - Apr 2008

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Sirolimus
Heterografts
Pediatrics
Neoplasms
TOR Serine-Threonine Kinases
Rhabdoid Tumor
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Cell Line
Rhabdomyosarcoma
Osteosarcoma
Growth
Sarcoma
Antineoplastic Agents
T-Lymphocytes
In Vitro Techniques

Keywords

  • Developmental therapeutics
  • Preclinical testing
  • Rapamycin

ASJC Scopus subject areas

  • Cancer Research
  • Pediatrics, Perinatology, and Child Health
  • Hematology

Cite this

Houghton, P. J., Morton, C. L., Kolb, E. A., Gorlick, R., Lock, R., Carol, H., ... Smith, M. A. (2008). Initial testing (stage 1) of the mTOR inhibitor rapamycin by the pediatric preclinical testing program. Pediatric Blood and Cancer, 50(4), 799-805. https://doi.org/10.1002/pbc.21296

Initial testing (stage 1) of the mTOR inhibitor rapamycin by the pediatric preclinical testing program. / Houghton, Peter J.; Morton, Christopher L.; Kolb, E. Anders; Gorlick, Richard; Lock, Richard; Carol, Hernan; Reynolds, C. Patrick; Maris, John M.; Keir, Stephen T.; Billups, Catherine A.; Smith, Malcolm A.

In: Pediatric Blood and Cancer, Vol. 50, No. 4, 04.2008, p. 799-805.

Research output: Contribution to journalArticle

Houghton, PJ, Morton, CL, Kolb, EA, Gorlick, R, Lock, R, Carol, H, Reynolds, CP, Maris, JM, Keir, ST, Billups, CA & Smith, MA 2008, 'Initial testing (stage 1) of the mTOR inhibitor rapamycin by the pediatric preclinical testing program', Pediatric Blood and Cancer, vol. 50, no. 4, pp. 799-805. https://doi.org/10.1002/pbc.21296
Houghton, Peter J. ; Morton, Christopher L. ; Kolb, E. Anders ; Gorlick, Richard ; Lock, Richard ; Carol, Hernan ; Reynolds, C. Patrick ; Maris, John M. ; Keir, Stephen T. ; Billups, Catherine A. ; Smith, Malcolm A. / Initial testing (stage 1) of the mTOR inhibitor rapamycin by the pediatric preclinical testing program. In: Pediatric Blood and Cancer. 2008 ; Vol. 50, No. 4. pp. 799-805.
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AU - Lock, Richard

AU - Carol, Hernan

AU - Reynolds, C. Patrick

AU - Maris, John M.

AU - Keir, Stephen T.

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N2 - Background. Rapamycin is a highly specific inhibitor of mTOR, a serine/threonine kinase that controls cap-dependent translation. Here we report the activity of rapamycin against the in vitro and in vivo panels of the Pediatric Preclinical Testing Program (PPTP). Procedures. Rapamycin was tested against the in vitro panel at concentrations from 0.01 to 100 nM and was tested against the in vivo tumor panels by i.p. administration daily x 5 for 6 consecutive weeks at a dose of 5 mg/kg. Results. Rapamycin variably inhibited growth of the cell lines in the PPTP in vitro panel, with maximal inhibition values ranging from 19% to 85% (median 49%) and a median EC50 of 0.7 nM. Ten of 23 cell lines achieved at least 50% growth inhibition. Against the in vivo panels, rapamycin induced significant differences in EFS distribution in 27 of 36 solid tumor xenografts and in 5 of 8 ALL xenografts. Using the time to event activity measure, rapamycin had intermediate or high activity against 14 of 31 evaluable solid tumor xenografts and 5 of 8 ALL xenografts. Objective responses were observed in several panels, including: rhabdoid tumor (IPR), rhabdomyosarcoma (2PR), and osteosarcoma (1 maintained CR). Two T-cell ALL xenografts had objective responses (1PR, 1 maintained CR). Conclusions. Rapamycin demonstrated broad antitumor activity against the PPTP's in vivo tumor panels, with particularly noteworthy activity for selected sarcoma and ALL xenografts. Future work will evaluate the molecular characteristics of responding models and the activity of combinations of rapamycin with other anticancer agents.

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