Signature-Based Small Molecule Screening Identifies Cytosine Arabinoside as an EWSFLI Modulator in Ewing Sarcoma 英文参考文献.docVIP

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Signature-Based Small Molecule Screening Identifies Cytosine Arabinoside as an EWSFLI Modulator in Ewing Sarcoma 英文参考文献.doc

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Signature-Based Small Molecule Screening Identifies Cytosine Arabinoside as an EWSFLI Modulator in Ewing Sarcoma 英文参考文献

o PL SMEDICINE Signature-BasedSmallMoleculeScreening IdentifiesCytosineArabinosideas anEWS/FLIModulatorinEwingSarcoma Kimberly Stegmaier1,2,Jenny S.Wong1,3,Kenneth N.Ross2,Kwan T.Chow1,David Peck2,Renee D.Wright1, Stephen L.Lessnick4,Andrew L.Kung1,Todd R.Golub1,2,3* 1DepartmentofPediatricOncology,Dana-FarberCancerInstituteandChildren’sHospitalBoston,HarvardMedicalSchool,Boston,Massachusetts,UnitedStatesofAmerica, 2TheBroad Institute ofHarvardUniversity andMassachusetts Institute ofTechnology, Cambridge,Massachusetts, UnitedStates ofAmerica, 3Howard HughesMedical Institute,HarvardMedicalSchool,Boston,Massachusetts,UnitedStatesofAmerica,4TheCenterforChildren,HuntsmanCancerInstitute,UniversityofUtah,SaltLakeCity, Utah,UnitedStatesofAmerica Funding:Thisworkwassupported bytheStevenandBonnieStern ResearchFund(TRG),aChildHealth ResearchGrantfromtheCharlesH. HoodFoundation(KS),andby NationalCancerInstituteKO8 CA96755(SLL).Thefundershadno roleinthestudydesign,data collectionandanalysis,decisionto publish,orpreparationofthe manuscript. ABSTRACT Background The presence of tumor-specific mutations in the cancer genome represents a potential opportunityforpharmacologicinterventiontotherapeuticbenefit.Unfortunately,manyclasses ofoncoproteins(e.g.,transcriptionfactors) arenotamenabletoconventionalsmall-molecule screening.Despitetheidentificationoftumor-specificsomaticmutations,mostcancertherapy still utilizes nonspecific, cytotoxic drugs. One illustrative example is the treatment of Ewing sarcoma.AlthoughtheEWS/FLIoncoprotein,presentinthevastmajorityofEwingtumors,was characterizedovertenyearsago,ithasneverbeenexploitedasatargetoftherapy.Previously, thistargethasbeenintractabletomodulationwithtraditionalsmall-moleculelibraryscreening approaches.Herewedescribeageneexpression–basedapproachtoidentifycompoundsthat induce a signature of EWS/FLI attenuation. We hypothesize that screening small-molecule libraries highly enriched for FDA-approved drugs will provide a more rapid