The insulin-like growth factor-1 receptor-targeting antibody, CP-751,871, suppresses tumor-derived VEGF and synergizes with rapamycin in models of childhood sarcoma.
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 (Tyr1131) that was blocked by CP751,871. In vivo CP-751,871, rapamycin, or the combination were 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 of 13 xenografts and induced complete remissions in one model each of rhabdomyosarcoma and EWS, and in three of four osteosarcoma models. CP751,871 caused complete IGF-1R down-regulation, suppression of AKT phosphorylation, and dramatically suppressed tumor-derived vascular endothelial growth factor (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.
Kurmasheva
Raushan T
RT
Departments of Molecular Pharmacology, Biostatistics, and Pathology, St. Jude Children's Research Hospital, Memphis, TN38105, USA.
Dudkin
Lorina
L
Billups
Catherine
C
Debelenko
Larisa V
LV
Morton
Christopher L
CL
Houghton
Peter J
PJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002648:Child; D004357:Drug Synergism; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D016513:Mice, SCID; D046912:Multiprotein Complexes; D012516:Osteosarcoma / Q000188:drug therapy / Q000378:metabolism; D011506:Proteins; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000276:immunology*; D012208:Rhabdomyosarcoma / Q000188:drug therapy / Q000378:metabolism; D012509:Sarcoma / Q000188:drug therapy* / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D016756:Immunoglobulins, Intravenous; D046912:Multiprotein Complexes; D011506:Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D017526:Receptor, IGF Type 1; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; C525021:figitumumab; D020123:Sirolimus