ABSTRACT Prognosisforchildrenandyoungadultswithmetastatic,relapsed,orrefractorysolidtumorsremains unacceptablypoorandhasnotimprovedsignificantlyoverthepastthreedecadesdespitemultimodality treatmentincludingsurgery,radiation,andchemotherapy.Currentapproacheshavereachedthelimitsof maximaldoseintensification,andtheacuteandlateeffectsofcombinationtherapyaresubstantial.Thegoalof thisproposalistoimprovethecurerateandqualityoflifeinpediatriccancerpatientsthroughapproachesthat maximizeeffectsofcurrenttherapywhileminimizingassociatedcomplications. Magneticresonance-guidedhighintensityfocusedultrasound(MR-HIFU)providescontrolleddeliveryof heatthroughpreciseimageguidance,real-timetemperaturemapping,andspatiallywell-defineddepositionof energyusinganexternalapplicatorthatiscompletelynon-invasiveandnon-ionizing.Lyso-thermosensitive liposomaldoxorubicin(LTLD)isaheat-activatedformulationofliposomaldoxorubicinwiththeuniqueproperty ofheat-activatedreleaseofdoxorubicin,anactiveagentinmostpediatricsolidtumors.Theflexibilityand controloverlowtemperaturelocalheatinginducedbyMR-HIFUprovidesanidealsystemtobeusedin conjunctionwithLTLD.Mathematicalmodelingandstudiesinrodentsdemonstratedthatoverallexposureof targetedtissuetodrugcanbesignificantlyenhancedbypulseofhighertemperatureheating(++)following drugreleasefromLTLDtriggeredbyMR-HIFUmildhyperthermia(40?45C,HT++).Theheatingpulseis thoughttonotonlypreventdrugwashout,butalsototargetthosepartsofthetumorthatmaynotbeexposed toasufficientquantityofdrug.Thesynergisticeffectsofthistherapyaremanifoldandincludeenhanced permeabilityofthetumorvasculature,enhancedextravasationofthedrugandsubsequenthighconcentrations ofdoxorubicininthetargetedtumor,theexpressionofheatshockproteins,inhibitionofDNArepair,and stimulationofimmuneresponses. Weproposetoaddresstheclinicalchallengesposedbyadvancedlocaldiseasethrougharobustbenchto bedsideproposalthatcombinesthestrengthsofboththeintramuralandextramuralteams.Wewillfirst evaluatetherelativeabilityofthiscombinationtoimprovethehomogeneityandoveralllevelsofdrugdelivery inpreclinicalrabbitVx2tumormodelthatislargeenoughtoallowforprecisespatialcontrolofheatingwith MR-HIFU.WewillevaluatetheimpactofLTLDcombinedwithMR-HIFUmildhyperthermiaandheatingpulse onvasculatureandnervetissuefunction,itsinfluenceonhostimmuneresponseanditsimpactontumor growthdelayandmetastasisoutsideoftreatmentfieldinthesamepre-clinicalmodel.Followingacomparative studyofeffectsinthepre-clinicalmodel,wewillevaluatethesafetyandclinicalbenefitofLTLD-HT++inPhase IIclinicaltrialenrollingchildrenandyoungadultswithrefractorysolidtumors.