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


METHODS
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 EC(50) 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).


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.
Houghton
Peter J
PJ
St. Jude Children's Research Hospital, Memphis, Tennessee, USA. peter.houghton@stjude.org
Morton
Christopher L
CL
Kolb
E Anders
EA
Gorlick
Richard
R
Lock
Richard
R
Carol
Hernan
H
Reynolds
C Patrick
CP
Maris
John M
JM
Keir
Stephen T
ST
Billups
Catherine A
CA
Smith
Malcolm A
MA
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D020123:Sirolimus / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000903:Antibiotics, Antineoplastic; D020123:Sirolimus