循环肿瘤细胞最新进展.ppt
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循环肿瘤细胞最新进展.ppt
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ExvivocultureofcirculatingbreasttumorcellsforindividualizedtestingofdrugsusceptibilityLiuZixinDepartmentofHepaticSurgeryVI,EHBH2015-01-05ReportContentCTC-iChipsystemandCTCculturetheIdentificationofCTCGenemutationanalysisDrugsensitivityConclusionDiscussionKnowledgeonCTC-iChipsystemlBiomarkersCTC:
EpCAM(+)whitebloodcells:
CD45(+)andCD66(+)lBasicmodes:
positiveselectionmode:
anti-EpCAMnegativeselectionmode:
anti-CD45anti-CD66CTC-iChipsystemCombinesthestrengthsofmicrofluidicsforrarecellhandingandmagnetic-basedcellsorting.lMagneticlabelingofcellsinbloodcells.(pos-vsneg-)lDebulkingbyseparationofnucleatedcellsfromtheenucleated.lAlignmentofnucleatedcellswithinamicrofluidicchannel.lDeflectionofmagneticallytaggedcellsintoacollectionchannel.TheSpecialconditionsforCTCcultrueBloodsamples:
patientswithmetastaticER(+)Nonadherentcultureconditions(critical)Serum-freesupplementedEGFandFGFunderhypoxicconditions(4%O2)Establishlong-termoligoclonalCTC(sustaimedinvitro6months)ResultsofCTCculturelCTClinescanonlybegeneratedfrompatientswhowereeitherofftherapyorprogressingontreatment.andcannotbegeneratedfrompatientswhowererespondingtotreatment.lForthreepatients,fouradditionalCTCcelllineswereestablishedfrombloodsamplesdrawnatmultipledifferenttimepointsduringtherapy.Inthesecases,CTCswereculturedonlywhenpatientswereprogressingontreatment.ResultsofCTCculturelCulturedCTCssharedcytologicalfeatureswiththematchedprimaryCTCscaptured.lConsisitentwithstandardCTCdefinitions:
CK(+);CD45(-);proliferativeindex30%(Ki67);initialdoublingtime:
3daysto3weeks.lFiveCTClinesretainedER(+),BRx-07lostERexpresion,butregainedinXenografttumor.lCTC-derivedtumorssharedhistologicalandimmunohistochemicalfeatureswiththematchedprimarytumor.GeneanalysislRNAsequencinganalysis6culturedcelllines;13commonlyusedbreastcancercelllines;29uncluredsingleCTCs.lMutationanalysisSNaPShot:
primarytumor(140mutationsin25gene)NGSplatform:
CTCcultureandothermutation(1000genes)ResultsofgeneanalysisESR1(BRx-68),TP53(BRx-68,61)andKRAS(BRx-42)areuniversallypresentinallindependentCTCcelllines.PIK3CA,KRASandFGFR2arearisingmutations.ThemutantallelefrequencesofTP53andESR1areincreaseduponprolongedculture.ChoosedrugtargetsESR1andPIK3CAfordrugsensitivitytest.ResultsofDrugSensitivitytestSomeCTCdrugsensitivitymeasurementswereconcordantwithclinicalhistory.ResultsofDrugSensitivity(BRx-68)SERMs(tamoxifen)andSERD(raloxifene)wereineffective,aloneorcombinedwithinhibitorsofPIK3-mTOR(everolimus).HSP90inhibitorSTA9090demonstratedcytotoxicity,aloneorcombinitionwithSERMsorSERD.AlowdoseofSTA9090suppressedERlevel.?
ResultsofDrugSensitivity(BRx-07)CulturedCTCswerehighlysensitivetoPIK3CAandFGFR2inhibitors.CombinationsofPIK3CAandFGFRinhibitorsshowedcooperatoveeffects.?
iIGFRmitigatesensitivitytoiPI3K;iHSP90stablizemutantkinases.ResultsofDrugSensitivity(BRx-07)DifferentFGFRmutationshavedifferentsensitivitytoPIK3CAandFGFR2inhibitors.ConclusionsStudypatternsofdrugsusceptibilitywithCTC,combinedwithgeneticcontext.Enablemonitoringofemergingsubcloneswithalterdmutationalanddrugsensitivityprofiles.DiscussionlSamples:
patientswithmetastatic/PVTTwhichstage?
lMode:
negativemode.lDrugtargets:
mutationalgeneanalysisLiuZixinwhichstage?
biomarkers?
AFP?
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