Novel Agents Targeting the IGF-1RPI3K Pathway Impair Cell Proliferation and Survival in Subsets of Medulloblastoma and Neuroblastoma 英文参考文献.docVIP

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Novel Agents Targeting the IGF-1RPI3K Pathway Impair Cell Proliferation and Survival in Subsets of Medulloblastoma and Neuroblastoma 英文参考文献.doc

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Novel Agents Targeting the IGF-1RPI3K Pathway Impair Cell Proliferation and Survival in Subsets of Medulloblastoma and Neuroblastoma 英文参考文献

NovelAgentsTargetingtheIGF-1R/PI3KPathwayImpair CellProliferationandSurvivalinSubsetsof MedulloblastomaandNeuroblastoma AnnaWojtalla1,FabianaSalm1,DitteG.Christiansen1,TizianaCremona2,PaulinaCwiek1, TarekShalaby2,NicoleGross3,MichaelA.Grotzer2,AlexandreArcaro1* 1Division of Pediatric Hematology/Oncology, Department of Clinical Research, University of Bern, Bern, Switzerland, 2Department of Oncology, University Children’s HospitalZurich,Zurich,Switzerland,3DepartmentofPediatrics,PediatricOncologyResearch,UniversityHospitalCHUV,Lausanne,Switzerland Abstract Thereceptortyrosinekinase(RTK)/phosphoinositide3-kinase(PI3K)pathwayisfundamentalforcancercellproliferationand isknowntobefrequentlyalteredandactivatedinneoplasia,includingembryonaltumors.Basedonthehighfrequencyof alterations,targetingcomponentsofthePI3Ksignalingpathwayisconsideredtobeapromisingtherapeuticapproachfor cancertreatment.Here,wehaveinvestigatedthepotentialoftargetingtheaxisoftheinsulin-likegrowthfactor-1receptor (IGF-1R)andPI3Ksignalingintwocommoncancersofchildhood:neuroblastoma,themostcommonextracranialtumorin children and medulloblastoma, the most frequent malignant childhood brain tumor. By treating neuroblastoma and medulloblastomacells withR1507,aspecifichumanizedmonoclonalantibody againsttheIGF-1R, wecould observecell line-specificresponsesandinsomecasesastrongdecreaseincellproliferation.Incontrast,targetingthePI3Kp110awith thespecificinhibitorPIK75resultedinbroadanti-proliferativeeffectsinapanelofneuro-andmedulloblastomacelllines. Additionally, sensitization to commonly used chemotherapeutic agents occurred in neuroblastoma cells upon treatment with R1507 or PIK75. Furthermore, by studying the expression and phosphorylation state of IGF-1R/PI3K downstream signaling targets we found down-regulated signaling pathway activation. In addition, apoptosis occurred in embryonal tumorcellsaftertreatmentwithPIK75orR1507.Together,ourstudiesdemonstratethepotentialoftargetingtheIGF-1R/ PI3Ksignalingaxis