Initial testing (stage 1) of the IGF-1 receptor inhibitor BMS-754807 by the pediatric preclinical testing program.


Journal Article

BACKGROUND: BMS-754807 is a small molecule ATP-competitive inhibitor of the type-1 insulin-like growth factor receptor currently in phase 1 clinical trials. PROCEDURES: BMS-754807 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro panel at concentrations ranging from 1.0 nM to 10 µM and was tested against the PPTP in vivo panels at a dose of 25 mg/kg administered orally BID for 6 days, repeated for 6 weeks. RESULTS: In vitro BMS-754807 showed a median EC(50) value of 0.62 µM against the PPTP cell lines. The median EC(50) for the four Ewing sarcoma cell lines was less than that for the remaining PPTP cell lines (0.19 µM vs. 0.78 µM, P = 0.0470). In vivo BMS-754807 induced significant differences in EFS distribution compared to controls in 18 of 32 evaluable solid tumor xenografts (56%) tested, but in none of the ALL xenografts studied. Criteria for intermediate activity for the time to event activity measure (EFS T/C > 2) were met in 7 of 27 solid tumor xenografts evaluable for this measure. The best response was PD2 (progressive disease with growth delay), which was observed in 18 of 32 solid tumor xenografts. PD2 responses were most commonly observed in the rhabdomyosarcoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and Wilms tumor panels. CONCLUSIONS: BMS-754807 activity in vitro is consistent with a specific IGF-1R effect that has half-maximal response in the 0.1 µM range and that is observed in a minority of the PPTP cell lines. In vivo intermediate activity was most commonly observed in the neuroblastoma and rhabdomyosarcoma panels.

Full Text

Duke Authors

Cited Authors

  • Kolb, EA; Gorlick, R; Lock, R; Carol, H; Morton, CL; Keir, ST; Reynolds, CP; Kang, MH; Maris, JM; Billups, C; Smith, MA; Houghton, PJ

Published Date

  • April 2011

Published In

Volume / Issue

  • 56 / 4

Start / End Page

  • 595 - 603

PubMed ID

  • 21298745

Pubmed Central ID

  • 21298745

Electronic International Standard Serial Number (EISSN)

  • 1545-5017

Digital Object Identifier (DOI)

  • 10.1002/pbc.22741


  • eng

Conference Location

  • United States