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.

Public Health Relevance

Significantacuteandlateside-effectsofcurrenttherapylimitanyfurthertreatmentintensificationfor patientswithmalignantsolidtumors.Theseclinicalchallengesmaybeaddressedwithacombinationofmild hyperthermiaheating(HT)viamagneticresonance-guidedhighintensityfocusedultrasound(MR-HIFU)and heat-triggereddrugdeliverywithlyso-thermosensitiveliposomaldoxorubicin(LTLD).However,thisdrug-device combination(LTLD-HT)mustbefurtheroptimizedpriortoclinicaluse.Inabench-to-bedsideapproach,weproposeto firstoptimizedrugdeliverywiththiscombinationoftechnologiesinpre-clinicalstudies,examiningitsutilityin sparingnearbycriticaltissuesaswellasitssystemicandlocalantitumoreffect.Havingoptimizedthemethod, weplantotestitsefficacyinaPhaseIIclinicaltrial.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA202947-02
Application #
9567102
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Zhang, Yantian
Project Start
2017-09-18
Project End
2021-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost

  Institution

Name
Children's Research Institute
Department
Type
DUNS #
143983562
City
Washington
State
DC
Country
United States
Zip Code
20010