NDLI: The IGF-1 Receptor Targeting Antibody, CP-751,871, Suppresses Tumor-Derived VEGF and Synergizes with Rapamycin in Models of Childhood Sarcoma

Content Provider	PubMed Central
Author	Kurmasheva, Raushan T. Dudkin, Lorina Billups, Catherine Debelenko, Larisa V. Morton, Christopher L. Houghton, Peter J.
Abstract	Signaling through the type 1 insulin-like growth factor receptor (IGF-1R) occurs in many human cancers, including childhood sarcomas. As a consequence, targeting the IGF-1R has become a focus for cancer drug development. We examined the antitumor activity of CP-751,871, a human antibody that blocks IGF-1R ligand binding, alone and in combination with rapamycin against sarcoma cell lines in vitro and xenograft models in vivo. In Ewing sarcoma (EWS) cell lines CP751,871 inhibited growth poorly (<50%), but prevented rapamycin-induced hyperphosphorylation of AKT(Ser473) and induced greater than additive apoptosis. Rapamycin treatment also increased secretion of IGF-1 resulting in phosphorylation of IGF-1R (Tyr1136) that was blocked by CP751,871. In vivo CP-751,871, rapamycin or the combination waere evaluated against EWS, osteosarcoma and rhabdomyosarcoma xenografts. CP751871 induced significant growth inhibition (EFS(T/C) >2) in four models. Rapamycin induced significant growth inhibition (EFS(T/C) >2) in nine models. Although neither agent given alone caused tumor regressions. in combination these agents had greater than additive activity against 5/13 xenografts and induced complete remissions (CR) in one model each of rhabdomyosarcoma and Ewing sarcoma, and in three of four osteosarcoma models. CP751,871 caused complete IGF-1R downregulation, suppression of AKT phosphorylation and dramatically suppressed tumor-derived VEGF in some sarcoma xenografts. Rapamycin treatment did not markedly suppress VEGF in tumors and synergized only in tumor lines where VEGF was dramatically inhibited by CP751,871. These data suggest a model in which blockade of IGF-1R suppresses tumor-derived VEGF to a level where rapamycin can effectively suppress the response in vascular endothelial cells.
Related Links	http://dx.doi.org/10.1158/0008-5472.can-09-1693
Ending Page	7671
Page Count	10
Starting Page	7662
File Format	PDF
ISSN	00085472
e-ISSN	15387445
Journal	Cancer research
Issue Number	19
Volume Number	69
Language	English
Publisher Date	2009-10-01
Access Restriction	Open
Subject Keyword	Cancer Research Oncology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology

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