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hERG1channels:froman2targetstonoveltherapeu2ctargetsinoncology
AnnarosaArcangeli1,AndreaBecche-2,OliviaCrociani,MassimoD’Amico1,LucaGasparoli1,MarikaMasselli,SerenaPillozzi1,KennethMugridge3andWolfgangTiedke3.
1DepartmentofExperimentalPathologyandOncology,UniversityofFlorenceandIsPtutoToscanoTumori(ITT),Florence,Italy;2DepartmentofBiotechnologyandBiosciences,
UniversityofMilanoBicocca,Milano,Italy;3BlackSwanPharmaGmbH,Leipzig,Germany.
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Disclosures
• Noconflictofinteresttodeclare
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hERG1POTASSIUMCHANNELS
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SeveraldrugsblockhERG1channels
drug‐inducedLQT2
ANTITARGET
SpecifichERG1blockersE4031WAY123,398
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‐ AcutemyeloidandlymphoblasPcleukemiasHofmannetal.,J.Biol.Chem.,2001;Pillozzietal.,Leukemia,2002;Pillozzietal.,Blood,2007;Pillozzietal.,Blood,2011
‐ EndometrialCancersCherubinietal.,Br.J.Cancer,2000
‐ NeuroblastomasArcangelietal.,J.CellBiol.,1993;Arcangelietal.,J.Physiol.,1995;Arcangelietal.,Eur.J.Neurosci,1997;Crocianietal.,Mech.Devel.,2000;Crocianietal.,J.Biol.Chem.,2003
‐ ColorectalandGastricCancersLastraiolietal.,CancerRes.2004;Lastraiolietal.,J.Cell.Physiol.,2006.
‐ GlioblastomaMasietal.,Br.J.Cancer,2005.
hERG1isoverexpressedinseveraltypesofhumancancers
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hERG1regulatesdifferentbiologicalfunc2onsincancercells
• Cellprolifera2on(myeloidleukemias)
• Drug‐inducedapoptosis(lymphoblas2cleukemias)• Tumorcellinvasionandmetasta2cspread(colorectalcancers)
• Trans‐endothelialmigra2onandinvasionofextra‐medullaryorgans(myeloidleukemias)
• VEGF‐Asecre2onandangiogenesis(astrocytomas;gastricandcolorectalcancers)
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hERG1:
newtargetinoncology?
Adversecardiaceffects!
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Differencesbetween“cardiac”and“tumour”hERG1
• Biophysical• Molecular
• FuncPons
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BiophysicalcharacterisPcsofhERG1channels
I(K)ERGquicklyinac2vatesaferopeningatposi2vepoten2alsInac2va2onisfasterthanac2va2onRecoveryfrominac2va2onisfasterthandeac2va2on
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Membranepoten2al
• Intheheart:hERG1=Ikr• hERG1channelsac2vateslowlyandinac2vaterapidlyduringtheini2alphasesofthecAP;asrepolariza2onbegins,hERG1channelsrapidlyrecoverfrominac2va2onandgenerateanappreciableoutwardcurrent.• Incancercells:• hERG1channelsexibitasignificantsteady–stateconductanceatmembranepoten2alsaround‐40mV
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Molecularcharacteris2csofhERG1incancercells
A
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Func2onsofhERG1incancercells
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hERG1channelsco‐assemblewithintegrinsandmodulateintegrin‐dependentsignalling.
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PotenPalapproachestoimprovetheefficacyandsafetyofhERG1channel
targePnginoncology:
‐Useof“non‐torsadogenic”hERG1blockers(e.g.erythromycin,ser2ndole).‐ UseofcompoundswhichbindhERG1channelsintheopenstate(D‐Roscovi2ne).‐ Use/developmentofcompoundswhichselec2velyinhibittumour‐specifichERG1isoform(s)‐Developmentofcompounds(an2bodies,pep2des)whichdisassembletheionchannel/integrincomplex.
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PotenPalapproachestoimprovetheefficacyandsafetyofhERG1channel
targePnginoncology:
‐Useof“non‐torsadogenic”hERG1blockers(e.g.erythromycin,ser2ndole).‐ UseofcompoundswhichbindhERG1channelsintheopenstate(D‐Roscovi2ne).‐ Use/developmentofcompoundswhichselec2velyinhibittumour‐specifichERG1isoform(s)‐Developmentofcompounds(an2bodies,pep2des)whichdisassembletheionchannel/integrincomplex.
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ErythromycinSer2ndole
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State‐dependentblockofHERGpotassiumchannelsbyR‐roscovi)ne:
implicaPonsforcancertherapy
GanapathiSBetal.,AmJPhysiolCellPhysiol296:C701–C710,2009.
R‐RoscoviPne
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SerenaPillozzi
SURVIVAL (ILK, AKT)
β1/hERG1/CXCR4 complex
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Thecomplexisrelevanttodrivesurvivalsignals
whichistheeffectofblockinghERG1channelsondrug‐inducedapoptosis?
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apop
to2ccells(%
)(Ann
exin+/PI‐)
TheaddiPonofhERG1blockersshortcomestheprotecPveeffectofBoneMarrowStromalCellsonDoxorubicin(Prednisone,Methotrexate,L‐asparaginase)‐induced
apoptosis
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PrimaryB‐ALL
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E4031synergizeswithchemotherapeu2cdrugs……onMSC
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EffectsofthehERG1blockerE4031invivo
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E4031hasatherapeu2ceffectinvivoonB‐ALL(697cells):increasein
survival
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E4031hasatherapeu2ceffectinvivoonB‐ALL(cor2costeroid‐resistantREH
cells)
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NontorsadogenichERG1blockers(ErythromycinandSer2ndole)andR‐
Roscovi2nehavethesameeffectsofE4031
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EffectsofErythromycinonprimaryB‐ALL
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PotenPalapproachestoimprovetheefficacyandsafetyofhERG1channel
targePnginoncology:
‐Useof“non‐torsadogenic”hERG1blockers(e.g.erythromycin,ser2ndole).‐ UseofcompoundswhichbindhERG1channelsintheopenstate(D‐Roscovi2ne).‐ Use/developmentofcompoundswhichselec2velyinhibittumour‐specifichERG1isoform(s)‐Developmentofcompounds(an2bodies,pep2des)whichdisassembletheionchannel/integrincomplex.
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Leipzig,Germany
W.Tiedke
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EffectsofCD‐160130onprolifera2onofleukemiacelllinesandhERG1A/hERG1B‐expressingcells:LD50
values(comparisonwithE4031)
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MassimoD’AmicoLucaGasparoli
CD‐160130preferen2allyinhibitsthehERG1Bisoform(comparisonwithE4031)
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FLG29.1CellsIC501.2µM
CD‐160130preferen2allyblockshERG1Bisoform
…alsoinleukemiacells
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CD‐160130issynergicwithFludarabineonapoptosisofMEC1cells(CLL)onMSC
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• LessharmfulcompoundscanbedevelopedwhichblockhERG1
channelsincancercells.
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Acknowledgements:
Dr.AndreaBecche-UniversityofMilanoBicocca
Prof.EnzoWanke