Clin Cancer Res-2015-Amengual-4663-75

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1、PublishedOnlineFirstJune26,2015;DOI:10.1158/1078-0432.CCR-14-3068CancerTherapy:PreclinicalClinicalCancerResearchDualTargetingofProteinDegradationPathwayswiththeSelectiveHDAC6InhibitorACY-1215andBortezomibIsSynergisticinLymphoma1111JenniferE.Amengual,PaulJohannet,MaximilianLombardo,KellyZullo,2

2、211DanielaHoehn,GovindBhagat,LuigiScotto,XavierJirau-Serrano,1133DejanRadeski,JenniferHeinen,HongfengJiang,SergeCremers,451YuanZhang,SimonJones,andOwenA.O'ConnorAbstractPurpose:Pan-classhistonedeacetylase(HDAC)inhibitorsResults:Concentration–effectrelationshipsdefinedmaximalareeffectivetreatmen

3、tsforselectlymphomas.Isoform-selec-cytotoxicityat48hourswithIC50valuesrangingfrom0.9totiveHDACinhibitorsareemergingaspotentiallymore4.7mmol/L.Strongsynergywasobservedincombinationwithtargetedagents.HDAC6isaclassIIbdeacetylasethatfacil-bortezomib.TreatmentwithACY-1215ledtoinhibitionofitatesmisf

4、oldedproteintransporttotheaggresomefortheaggresomeevidencedbyacetylateda-tubulinandaccu-degradation.Weinvestigatedthemechanismandtherapeu-mulatedpolyubiquitinatedproteinsandupregulationofticimpactoftheselectiveHDAC6inhibitorACY-1215alonetheUPR.Allpharmacodynamiceffectswereenhancedwithandincomb

5、inationwithbortezomibinpreclinicalmodelstheadditionofbortezomib.Findingswerevalidatedinvivooflymphoma.wheremicetreatedwiththecombinationdemonstratedsigni-ExperimentalDesign:Concentration–effectrelation-ficanttumorgrowthdelayandprolongedoverallsurvival.shipsweredefinedforACY-1215across16lymphomac

6、ellEvaluationofacollectionofprimarylymphomasamplesforlinesandforsynergywithbortezomib.MechanismwasmarkersoftheUPRrevealedincreasedHDAC6,GRP78,andinterrogatedbyimmunoblotandflowcytometry.AninvivoXBP-1expressionascomparedwithreactivelymphoidtissue.xenograftmodelofDLBCLwasusedtoconfirminvitroConclu

7、sions:Thesedataarethefirstresultstodemonstratefindings.Acollectionofprimarylymphomasampleswerethatdualtargetingofproteindegradationpathwaysrepresentsansurveyedformarkersoftheunfoldedproteinresponseinnovativeandrationalapproachforthetreatm