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

Resultado de la investigación: Articlerevisión exhaustiva

145 Citas (Scopus)

Resumen

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.

Idioma originalEnglish (US)
Páginas (desde-hasta)799-805
Número de páginas7
PublicaciónPediatric Blood and Cancer
Volumen50
N.º4
DOI
EstadoPublished - abr. 2008
Publicado de forma externa

ASJC Scopus subject areas

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

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