R1507, an Anti-Insulin-Like Growth Factor-1 Receptor (IGF-1R) Antibody, and EWSFLI-1 siRNA in Ewings Sarcoma Convergence at the IGFIGFRAkt Axis 英文参考文献.docVIP

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R1507, an Anti-Insulin-Like Growth Factor-1 Receptor (IGF-1R) Antibody, and EWSFLI-1 siRNA in Ewings Sarcoma Convergence at the IGFIGFRAkt Axis 英文参考文献.doc

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R1507, an Anti-Insulin-Like Growth Factor-1 Receptor (IGF-1R) Antibody, and EWSFLI-1 siRNA in Ewings Sarcoma Convergence at the IGFIGFRAkt Axis 英文参考文献

R1507,anAnti-Insulin-LikeGrowthFactor-1Receptor (IGF-1R)Antibody,andEWS/FLI-1siRNAinEwing’s Sarcoma:ConvergenceattheIGF/IGFR/AktAxis HelenJ.Huang1.,LauraS.Angelo1.,JordiRodon1,2,MichaelSun1,Klaus-PeterKuenkele3,HenriqueA. Parsons1,JonathanC.Trent4,RazelleKurzrock1* 1PhaseIProgram,DepartmentofInvestigationalCancerTherapeutics,TheUniversityofTexasM.D.AndersonCancerCenter,Houston,Texas,UnitedStatesofAmerica, 2Serveid’OncologiaMedica,Valld’HebronInstituteofOncology,HospitalUniversitariValld’Hebron,Barcelona,Spain,3RocheDiagnosticsGmbH,Penzberg,Germany, 4DivisionofCancerMedicine,DepartmentofSarcomaMedicalOncology,TheUniversityofTexasM.D.AndersonCancerCenter,Houston,Texas,UnitedStatesofAmerica Abstract A subset of patients with Ewing’s sarcoma responds to anti-insulin-like growth factor-1 receptor (IGF-1R) antibodies. Mechanismsofsensitivityandresistanceareunknown.Weinvestigatedwhetherananti-IGF-1Rantibodyactsviaapathway thatcouldalsobesuppressedbysmallinterfering(si)RNAagainsttheEWS/FLI-1fusionprotein,thehallmarkofEwing’s sarcoma. The growth of two Ewing’s sarcoma cell lines (TC-32 and TC-71) was inhibited by the fully human anti-IGF-1R antibody,R1507(clonogenicandMTTassays).TC-32andTC-71cellsexpresshighlevelsofIGF-2,whileRD-ESandA4573 Ewing’scelllines,whichwerelessresponsivetoR1507inourassays,expressloworundetectableIGF-2,respectively.TC-71 cells also expressed high levels of IGF-1R, and R1507 decreased steady-state levels of this receptor by internalization/ degradation,aneffectwhichwasassociatedwithadecreaseinp-IGF-1R,p-IRS-1,andp-Akt.EWS/FLI-1siRNAalsodecreased p-Akt,duetoitsabilitytoincreaseIGF-BP3levelsandsubsequentlydecreaseIGF-1andIGF-2levels,thusinhibitingsignaling throughp-IGF-1R.Thisinhibitioncorrelatedwithgrowthsuppressionandapoptosis.TheattenuationofAktactivationwas confirmedinTC-71andHEK-293(humanembryonickidney)cellsbytransfectingthemwithIGF-1RsiRNA.Weconcludethat antibodies and siRNA to IGF-1R, as well as siRNA to EWS/FLI-1, act via intersecting IGF/IGF