In addition to the authors, the work is contributed by the following: Sherry Ansher, Leticia Campbell, Joshua Courtright, Edward Favours, Henry S. Friedman, Nino Keshelava, Tiebin Liu, Debbie Payne, Charles Stopford, Mayamin Tajbakhsh, Chandra Tucker, Maya Willie, Jianrong Wu, Joseph Zeidner, Wendong Zhang, and Jian Zhang.
Article first published online: 16 JUL 2007
Copyright © 2007 Wiley-Liss, Inc.
Pediatric Blood & Cancer
Volume 50, Issue 4, pages 799–805, April 2008
How to Cite
Houghton, P. J., Morton, C. L., Kolb, E. A., Gorlick, R., Lock, R., Carol, H., Reynolds, C. P., Maris, J. M., Keir, S. T., Billups, C. A. and Smith, M. A. (2008), Initial testing (stage 1) of the mTOR inhibitor rapamycin by the pediatric preclinical testing program. Pediatr. Blood Cancer, 50: 799–805. doi: 10.1002/pbc.21296
Children's Cancer Institute Australia for Medical Research is affiliated with the University of New South Wales and Sydney Children's Hospital.
- Issue published online: 19 FEB 2008
- Article first published online: 16 JUL 2007
- Manuscript Accepted: 29 MAY 2007
- Manuscript Received: 12 FEB 2007
- National Cancer Institute. Grant Numbers: NO1-CM-42216, CA21765, CA108786
- developmental therapeutics;
- preclinical testing;
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).
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 × 5 for 6 consecutive weeks at a dose of 5 mg/kg.
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 (1PR), rhabdomyosarcoma (2PR), and osteosarcoma (1 maintained CR). Two T-cell ALL xenografts had objective responses (1PR, 1 maintained CR).
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. Pediatr Blood Cancer 2008;50:799–805. © 2007 Wiley-Liss, Inc.