ESMO Annals of Oncology VOL27 2016 Supplement 09

203 Pages·2016·2.63 MB·English

Annals of Oncology
Official Journal of the European Society for Medical Oncology and
the Japanese Society of Medical Oncology
editor-in-chief: editorsemeriti Preclinicalandexperimentalscience
T.U.E.Helleday,Stockholm,Sweden
J.-C.Soria,Villejuif,France F.Cavalli,Bellinzona,Switzerland
D.J.Kerr,Oxford,UK Precisionmedicine
J.B.Vermorken,Edegem,Belgium C.Swanton,London,UK
associateeditors
Gynecologicaltumors Bioinformatics
Urogenitaltumors B.Monk,Phoenix,Arizona,USA N.McGranahan,London,UK
G.Attard,Sutton,UK S.Pignata,Naples,Italy
M.DeSantis,Birmingham,UK BioTechnologies
Melanoma E.Mardis,St.Louis,Missouri,USA
Gastrointestinaltumors G.Long,Sydney,Australia
D.Arnold,Lisbon,Portugal Onco-Immunology
Hematologicalmalignancies
A.Cervantes,Valencia,Spain G.Coukos,Lausanne,Switzerland
K.Tsukasaki,Kashiwa,Japan
J.Tabernero,Barcelona,Spain A.Snyder,NewYork,NewYork,USA
P.L.Zinzani,Bologna,Italy
Breasttumors Statistics
Supportivecare
F.Andr´e,Villejuif,France M.Buyse,Brussels,Belgium
K.Jordan,Halle,Germany
C.Sotiriou,Brussels,Belgium
Epidemiology Molecularandsurgicalpathology
Thoracictumors P.Boffetta,NewYork,NewYork,USA I.I.Wistuba,Houston,Texas,USA
T.Mitsudomi,Osaka,Japan
J.F.Vansteenkiste,Leuven,Belgium Sarcomaandclinicalpharmacology Annalsofoncologyonline
O.Mir,Villejuif,France C.Ferte´,Villejuif,France
Headandnecktumors
A.T.C.Chan,Shatin,HongKong Earlydrugdevelopment Industrycorner:perspectivesandcontroversies
E.Cohen,SanDiego,California,USA J.-C.Soria,Villejuif,France K.Dhingra,NewYork,NewYork,USA
editorialboard
M.S.Aapro,Genolier,Switzerland R.Govindan,St.Louis,Missouri,USA A.Ohtsu,Chiba,Japan
Y.Ando,Nagoya,Japan P.Grimison,Sydney,Australia I.Okamoto,Fukuoka,Japan
P.Autier,Lyon,France A.Grothey,Rochester,Minnesota,USA S.I.Ou,Orange,California,USA
H.A.AzimJr,Marseille,France S.Halabi,Durham,NorthCarolina,USA X.Paoletti,Paris,France
I.Barnes,Oxford,UK D.G.Haller,Philadelphia,Pennsylvania,USA C.Pezaro,Melbourne,Australia
J.Baselga,NewYork,USA K.Hotta,Okayama,Japan P.Pfeiffer,Odense,Denmark
J.Bellmunt,Boston,Massachusetts,USA R.A.Huddart,Sutton,UK S.V.Porceddu,Brisbane,Australia
B.Besse,Villejuif,France I.Hyodo,Tsukuba,Japan M.R.Posner,NewYork,USA
J.Beyer,Zurich,Switzerland M.Ignatiadis,Brussels,Belgium S.Postel-Vinay,Villejuif,France
P.Bierman,Omaha,Nebraska,USA D.H.Ilson,NewYork,NewYork,USA A.Psyrri,Athens,Greece
C.Bokemeyer,Hamburg,Germany H.Iwata,Aichi,Japan D.Quinn,LosAngeles,California,USA
N.Boku,Tokyo,Japan F.Janku,Houston,Texas,USA S.S.Ramalingam,Atlanta,Georgia,USA
F.Bretz,Basel,Switzerland N.Katsumata,Kawasaki,Japan M.Reck,Grosshansdorf,Germany
E.Bria,Verona,Italy N.Kiyota,Kobe,Japan B.Rini,Cleveland,Ohio,USA
E.F.Burgess,Charlotte,NorthCarolina,USA C.LaVecchia,Milan,Italy R.Rosell,Badalona,Spain
P.G.Casali,Milan,Italy P.N.JrLara,Sacramento,California,USA A.D.Roth,Geneva,Switzerland
F.Ciardiello,Naples,Italy S.Loi,Melbourne,Australia R.Salazar,Barcelona,Spain
A.Comandone,Turin,Italy S.Loibl,Neu-Isenburg,Germany M.Scartozzi,Ancona,Italy
P.G.Corrie,Cambridge,UK F.Lordick,Leipzig,Germany N.Schmitz,Hamburg,Germany
G.Curigliano,Milan,Italy Y.Loriot,Villejuif,France H.-J.Schmoll,Halle,Germany
A.DiLeo,Prato,Italy S.Lutzker,SanFrancisco,California,USA I.Sekine,Tsukuba,Japan
T.Dorff,LosAngeles,California,USA T.Macarulla,Barcelona,Spain Q.Shi,Rochester,Minnesota,USA
H.Dosaka-Akita,Sapporo,Japan M.Martin,Madrid,Spain A.F.Sobrero,Genoa,Italy
E.A.Eisenhauer,Kingston,Canada S.Matsui,Tokyo,Japan G.Sonpavde,Birmingham,Alabama,USA
A.Eniu,Cluj-Napoca,Romania J.Maurel,Barcelona,Spain S.Takahashi,Tokyo,Japan
T.Fenske,Milwaukee,Wisconsin,USA G.McArthur,Melbourne,Australia M.Toi,Kyoto,Japan
S.Galbraith,Cambridge,UK S.Michiels,Villejuif,France B.A.VanTine,St.Louis,Missouri,USA
G.Giamas,Brighton,UK H.Minami,Kobe,Japan E.Vilar,Houston,Texas,USA
R.Glynne-Jones,Northwood,UK Y.Nishimura,Osaka-Sayama,Japan Y.-L.Wu,Guangzhou,China
B.-C.Goh,Singapore,Singapore K.Nishio,Osaka-Sayama,Japan J.C.-H.Yang,Taipei,Taiwan
A.Goldhirsch,Milan,Italy M.Ogura,Gifu,Japan S.Yano,Kanazawa,Japan
executiveeditor:LewisRowett
editorial office: Vanessa Marchesi, Paola Minotti Bernasconi, Giovannella Porcu, Annals of Oncology, Via Luigi Taddei 4, CH-6962
Viganello-Lugano,Switzerland
AnnalsofOncologyiscoveredinC.A.B.International,CurrentClinicalCancer,CurrentContents/ClinicalMedicineVR,CurrentContents/Life
Sciences,ElsevierBIOBASE/CurrentAwarenessinBiologicalSciences,EMBASE/ExcerptaMedica,IBIDS,IndexMedicus/MEDLINE,The
InternationalMonitorinOncology,MedicalDocumentationService,ScienceCitationIndexVRandScienceCitationIndexExpanded.
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Annals of
Oncology
Official Journal of the European Society
for Medical Oncology and the Japanese
Society of Medical Oncology
Volume 27, 2016 Supplement 9
ESMOAsiaCongress
16–19December2016,Singapore
ABSTRACTBOOK
GuestEditors:
ESMOAsia2016ScientificCommittee
Annals of Oncology
Official Journal of the European Society for
Medical Oncology and the Japanese Society of Medical Oncology
Volume 27, 2016 Supplement 9
Abstract BookofESMO Asia Congress
Singapore, 16–19December 2016
AboutESMO ix-v Headandneckcancer ix112
ESMOAsia2016OfficersandScientificCommittee ix-vi Immunotherapyofcancer ix123
ESMOAsiaCongress2016Organisation ix-vii Melanomaandotherskintumours ix126
Acknowledgements ix-viii Neuroendocrinetumours ix130
Newdiagnostics ix132
Abstracts NSCLC,earlystage ix134
Basicscience ix1 NSCLC,locallyadvanced ix136
Biomarkers ix9 NSCLC,metastatic ix139
Breastcancer,earlystage ix19 Palliativecare ix157
Breastcancer,locallyadvanced ix30 Psycho-oncology ix161
Breastcancer,metastatic ix35 Sarcoma ix163
CNStumours ix42 SCLC ix169
Developmentaltherapeutics ix46 Supportivecare ix170
Endocrinetumours ix52 Thoracicmalignancies,other ix177
Gastrointestinaltumours,colorectal ix53 Translationalresearch ix179
Gastrointestinaltumours,non-colorectal ix68 Tumourbiologyandpathology ix181
Genitourinarytumours,non-prostate ix86 Generalinterest ix184
Genitourinarytumours,prostate ix90 Late-breakingabstracts ix190
Gynaecologicalcancers ix94 Drugindex ix192
Haematologicalmalignancies ix104 TranslationalResearchindex ix194
Note:Abstractsuffixes
“O”indicatesasubmittedabstractacceptedforProfferedPaper(oral)presentation
“PD”indicatesasubmittedabstractacceptedforPosterDiscussion
“P”indicatesasubmittedabstractacceptedforPosterPresentation
“TiP”indicatesasubmittedabstractacceptedforPosterPresentation,TrialinProgress
__PRindicatesasubmittedabstractselectedforinclusionintheESMOPressProgramme
Volume27|Supplement9|December2016
The European Society for Medical Oncology (ESMO)
ESMOistheleadingprofessionalorganisationformedicaloncology,withtheoverarchinggoalofimprovingoutcomesforcancerpa-
tientseverywhere.Wearethesocietyofreferenceforoncologyeducationandinformation,andarecommittedtosupportingourmem-
berstodevelopandadvanceinafast-evolvingprofessionalenvironment.
Foundedin1975,ESMOhasEuropeanrootswithaglobalreach:wewelcomeoncologyprofessionalsfromaroundtheworld.Wearea
homeforalloncologystakeholders,connectingprofessionalswithdiverseexpertiseandexperience,andspeakingwithonevoicefor
our discipline. Our educationandinformationresourcessupportan integrated multi-professional approachtocancer care, froma
medicaloncologyperspective.Weseektoeraseboundariesincancercare,whetherbetweencountriesorspecialities,andpursueour
missionacrossoncology,worldwide.
TheESMOcommunitybringstogetherover14,000oncologyprofessionalsfromover130countries.Drawingon40yearsofexperience
andaround500expertcommitteemembers,ESMOservesitsmembersandtheoncologycommunitythrough:
• Post-graduateoncologyeducationandtraining
• Careerdevelopmentandleadershiptrainingforthenextgenerationsofoncologists
• Internationalcongressesandworkshopstoshareexpertiseandbestpractice,learnaboutthemostup-to-datescientificadvances,
andconnectwithcolleaguesinrelateddisciplines.
• Continuouslyreviewed,evidence-basedstandardsforcancercareinEurope
• Advocacyandconsultationtofosterafavourableenvironmentforscientificresearch
Cancercareisrapidlybecomingmoreintegratedandmorespecialised;whethertheirfieldisresearch,diagnosis,treatment,care,orad-
vocacy,oncologyprofessionalsneedtobothbuildtheirspecialistknowledgeandconnectwiththebestpractitionersinotherdisciplines
worldwide.ESMOmembershipmakesthispossible.
Pleasevisitesmo.orgtolearnmore.AcrossOncology.Worldwide.
ESMO Executive Board 2016
President FortunatoCiardiello,Naples,Italy
President-Elect JosepTabernero,Barcelona,Spain
PastPresidentandMembershipCommitteeChair RolfA.Stahel,Zurich,Switzerland
Treasurer EmileVoest,Amsterdam,TheNetherlands
EducationalCommitteeChair Andre´sCervantes,Valencia,Spain
NationalRepresentativesandMembershipCommitteeChair FatimaCardoso,Lisbon,Portugal
EUPolicyCommitteeChair PaoloG.Casali,Milan,Italy
GlobalPolicyCommitteeChair AlexandruEniu,Cluj-Napoca,Romania
GuidelinesWorkingGroupChair GeorgePentheroudakis,Ioannina,Greece
PressandMediaAffairsCommitteeChair SolangePeters,Lausanne,Switzerland
PractisingOncologistsCommitteeChair StefanRauh,Luxembourg
BoardMember DirkArnold,Lisbon,Portugal
BoardMember AlexanderM.M.Eggermont,Villejuif,France
BoardMember JacekJassem,Gdansk,Poland
BoardMember ChristophZielinski,Vienna,Austria
ESMO Asia 2016 Officers
ESMOandCongressPresident
FortunatoCiardiello,Naples,Italy
ScientificCommitteeChair ScientificCo-Chair
RolfA.Stahel,Zurich,Switzerland HyunCheolChung,Seoul,RepublicofKorea
EducationalChair EducationalCo-Chair
Andre´sCervantes,Valencia,Spain Yi-LongWu,Guangzhou,China
LocalOfficer PressOfficer
RavindranKanesvaran,Singapore SolangePeters,Lausanne,Switzerland
Scientific Committee
Basicscienceandtranslationalresearch Breastcancer
Chair:RichardMarais,Manchester,UK Chair:RebeccaDent,Singapore
AntonBerns,Amsterdam,Netherlands FabriceAndre´,Villejuif,France
DavidHuang,Melbourne,Australia FatimaCardoso,Lisbon,Portugal
Seock-AhIm,Seoul,RepublicofKorea SungBaeKim,Seoul,RepublicofKorea
HitoshiNakagama,Tokyo,Japan ShereneLoi,Melbourne,Australia
RuthPalmer,Gothenburg,Sweden
JoanSeoane,Barcelona,Spain
SheilaSingh,Hamilton,ON,Canada
BrittaWeigelt,NewYork,NY,USA
CNStumours Developmentaltherapeutics
Chair:MartinTaphoorn,Amsterdam,Netherlands Chair:Jean-PierreDelord,Toulouse,France
AlbaBrandes,Bologna,Italy DanielTan,Singapore
RakeshJalali,Mumbai,India JinLi,Shanghai,China
RyoNishikawa,Saitama,Japan LilianSiu,Toronto,ON,Canada
MichaelWeller,Zurich,Switzerland ViolettaSerra,Barcelona,Spain
OlivierRixe,Albuquerque,NM,USA
Gastrointestinaltumours Genitourinarytumours
Chair:DirkArnold,Lisbon,Portugal Chair:SunYoungRha,Seoul,RepublicofKorea
IanChau,Sutton,UK JoaquimBellmunt,Boston,MA,USA
TaeWonKim,Seoul,RepublicofKorea BernardEscudier,Villejuif,France
FlorianLordick,Leipzig,Germany IanDavis,Melbourne,Australia
AtsushiOhtsu,Kashiwa,Japan DanielY.C.Heng,Calgary,AL,Canada
TimothyPrice,Adelaide,Australia RavindranKanesvaran,Singapore
EricVanCutsem,Leuven,Belgium BinTeanTeh,Singapore
Gynaecologicalcancers Haematologicalmalignancies
Chair:MichaelFriedlander,Sydney,Australia Chair:Zhi-MingLi,Guangzhou,China
DavidBowtell,Melbourne,Australia ChristianBuske,Ulm,Germany
KeiichiFujiwara,Saitama,Japan WonSeogKim,Seoul,RepublicofKorea
JonathanLedermann,London,UK Yok-LamKwong,HongKong,China
CristianaSessa,Bellinzona,Switzerland OwenA.O’Connor,NewYork,NY,USA
DavidSPTan,Singapore Hui-LaiZhang,Tianjin,China
Headandneckcancer Immunotherapyofcancer
Chair:LisaLicitra,Milan,Italy Chair:JohnHaanen,Amsterdam,Netherlands
AnthonyT.C.Chan,HongKong,China YutakaKawakami,Tokyo,Japan
AnilD’Cruz,Mumbai,India TonyS.K.Mok,HongKong,China
VincentGre´goire,Brussels,Belgium HanChongToh,Singapore
HishamMehanna,Birmingham,UK
AmandaPsyrri,Athens,Greece
MakotoTahara,Tokyo,Japan
Melanomaandotherskintumours Sarcoma
Chair:GrantMcArthur,Melbourne,Australia Chair:AkiraKawai,Tokyo,Japan
JunGuo,Beijing,China Jean-YvesBlay,Lyon,France
GeorginaLong,Sydney,Australia PaoloG.Casali,Milan,Italy
PaulLorigan,Manchester,UK DaeGeunJeon,Seoul,RepublicofKorea
CarolineRobert,Villejuif,France RobinJones,London,UK
RogerNgan,HongKong,China
RichardQuek,Singapore
EdwardWang,Manila,Philippines
Supportive&palliativecare Thoraciccancers
Chair:KazuoTamura,Fukuoka,Japan Chair:CaicunZhou,Shanghai,China
MyungJuAhn,Seoul,RepublicofKorea
MattiAapro,Genolier,Switzerland
DirkDeRuysscher,Maastricht,Netherlands
AlexandreChan,Singapore
KeunchilPark,Seoul,RepublicofKorea
KarinJordan,Halle,Germany
GregoryJ.Riely,NewYork,NY,USA
Yeur-HurLai,Taipei,Taiwan
EgbertSmit,Amsterdam,Netherlands
IanOlver,Sydney,Australia
QingZhou,Guangzhou,China
TheEuropeanSocietyforMedicalOncologywishestoexpressitsappreciationandgratitudetoalloftheaboveexpertsfortheirmajor
efforttoselectthecontentofthisAbstractBook.
ESMO Asia Congress 2016 Organisation
Organisation ESMOHeadOffice
ViaLuigiTaddei4
CH-6962Viganello-Lugano
Switzerland
Tel. [phone]
Fax [phone]
E-mail [email protected]
www.esmo.org
Accommodation MCIGroupAsiaPacific
PCOConsultant
Singapore
Tel. [phone]
Fax [phone]
E-mail [email protected]
www.mci-group.com
Venue SuntecSingapore
InternationalConvention&ExhibitionCentre
1RafflesBoulevard
SuntecCity
Singapore
Tel. [phone]
Fax [phone]
www.suntecsingapore.com

AnnalsofOncology27(Supplement9):ix1–ix8,2016
doi:10.1093/annonc/mdw573
Basic science Methods:IBPRhasidentifiedaseriesofnovelcKITinhibitors,theBPRCKJseries,
whichexhibitedpotentcKITkinaseactivityinhibition.Toevaluatethepotentialof
BPRCKJcompoundsasnovelcKITinhibitorsagainstGIST,eightdifferentimatinib-
resistantmutatedcKITswereselectedtoexaminetheinhibitoryactivitiesofBPRCKJ
1PD Breastcancerblood-derivedexosomes:Characterisationof series.TheresultsshowedthatBPRCKJserieshasabroadspectrumactivityagainst
proteincompositioninsearchfornewbiomarkers variousformsofimatinib-resistantmutantc-KITs.Mostimportantly,theabilityto
overcomeimatinib-andsunitinib-resistantmutantcKITsisdemonstrated.
O.S.Tutanov1,S.N.Tamkovich1,A.Grigoryeva2,E.Ryabchikova2,T.Duzhak3, Results:ThroughthecomprehensiveSARstudy,wehadidentifiedBPRCKJ001asa
Y.Tsentalovich3,P.Laktionov1,V.Vlassov1 potentialcandidate,whichwasshowntostronglyinhibittheenzymaticactivitiesof
1LaboratoryofMolecularMedicine,InstituteofChemicalBiologyand severalmutantc-KIT.BPRCKJ001alsoeffectivelyinhibitedthreeGISTsensitiveand
FundamentalMedicineSBRAS,Novosibirsk,RussianFederation,2Groupof resistantcelllineswithIC50valuesbelow20nM.Itisinterestingtonotethat
Microscopy,InstituteofChemicalBiologyandFundamentalMedicineSBRAS, BPRCKJ001is10-timesand400-timesmorepotentthansunitinibinGIST430cellsand
Novosibirsk,RussianFederation,3GroupofProteomicsandMetabolomics, sunitinib-resistantcelllines(GIST48),respectively.TheWesternblotanalysesalso
InternationalTomographyCenterSBRAS,Novosibirsk,RussianFederation clearlyshowedthatBPRCKJ001cansuppressthecKITphosphorylationand
downstreamAKTphosphorylationmoreeffectivelythanimatinibandsunitinibin
GIST430cells.
Background:Exosomesareknowntobeinvolvedinthesignallingprocessesandcell- Conclusions:BPRCKJ001hadshownexcellentinvitroeffects,targetingagainstboth
to-cellcommunicationbothinhealthyorganismsandduringthedevelopmentof imatinib-andsunitinib-resistantmutantsinbothenzymaticandcellularsystems.More
variouscancertypes.However,theexactmechanismsofsortingandsecretingaswellas importantly,BPRCKJ001alsodemonstratedinvivoefficacybyoraladministrationin
thecirculationpatternsandcompositionofexosomesarestillunclear.Theaimofour GIST430xenograftmodel.TheseresultsindicatethatCKJBPR001serieshasreasonable
researchistoidentifyproteincontentofblood-derivedexosomesanddetermine pharmaceuticalpropertiestobedevelopedasapotentialcKITinhibitor
potentialbiomarkersspecificforbreastcancerdevelopment.Sinceexosomesare Legalentityresponsibleforthestudy:Weir-TornJiaang
naturallybindingwiththecells,wedecidedtoextractthemnotonlyfrombloodplasma Funding:MOEA,Taiwan
butalsofrombloodcellssurfaceinordertounderstandtheirpercentage,propertiesand
Disclosure:Allauthorshavedeclarednoconflictsofinterest.
composition.
Methods:Exosomesfrombloodplasmaandbloodcellsurface-boundexosomeswere
obtainedusingmethodsdevelopedinourlab(RFPatent#2556825,#2571507).The
3P Anti-VEGFandintegrin-linkedkinaseknockdowninhibit
resultantsampleswerecharacterizedbytransmissionelectronmicroscopy(TEM)and
angiogenesisinvitroandsuppressvasculartumorgrowthin
immunogoldlabelingtostatethepresenceofcharacteristicexosometetraspaninsCD-9,
vivo
CD-24andCD-63.Proteinsfromexosomesampleswereseparatedbyelectrophoresis
ingradientpolyacrylamidegelandidentifiedbyMALDI-TOFanalysis.
P.Mabeta
Results:Immunogoldlabelingconfirmedthepresenceofantigenscharacteristicfor
exosomes:CD-9,CD-24andCD-63.Theevaluationofparticlediameterof14950 Physiology,UniversityofPretoria,Pretoria,SouthAfrica s
t
exosomeshasshownthatthebloodofbreastcancerpatientsismostlypresentedwith c
a
exosomesdiameterfrom50to70nm,thebloodofhealthywomen-from30to50nm. r
Wediscoveredthat61%ofblood-derivedexosomesareboundtothesurfaceofblood Background:Angiogenesisistheprocessbywhichnewbloodvesselsareformed.Itis st
cells.MALDITOF/TOFidentifiedmorethan150proteinsinexosomesfromtheblood alsoakeyfeatureinthegrowthandprogressionofseveralcancers.Studieshave b
ofhealthywomen(n¼5)andbreastcancerpatients(n¼5),themajorityofwhichare identifiedvascularendothelialfactor(VEGF)asanimportantregulatorofangiogenesis a
foundinexosomesforthefirsttime(accordingExocartadatabaseatthesummerof inboththephysiologicalandpathologicalsettings.Inthecontextofcancer,VEGF
2016). signallingwasshowntobeimpairedinseveralneoplasms.Thisdiscoveryledtothe
Conclusions:Althoughitisstillunclearwhatleadstodifferencesinexosomesizein developmentoftherapiesagainstVEGF.WhileantiangiogenicVEGF-targetedtherapy
plasmaandonthesurfaceofthebloodcellstheresultssuggesttheimportanceofthis hasresultedinincreasedcancerpatientsurvival,thedevelopmentofresistancehas
exosomefractionandprovidesuswiththenewperspectiveinexosomeresearch. necessitatedthediscoveryofalternativeorcomplimentarytherapeuticstrategies.
Furtheranalysiswithexpandedsamplesizemayleadustobiomarkerpatternsaswellas Integrin-linkedkinase(ILK)isaneffectorofintegrin-mediatedcelladhesion.Itisalso
newinsightintoexosomestructure. involvedintheregulationofthePI3k/Aktpathway.
Legalentityresponsibleforthestudy:LaboratoryofMolecularMedicine,Instituteof Methods:TheeffectsofILKknockdownandanti-VEGFwereevaluatedonendothelial
ChemicalBiologyandFundamentalMedicineofSiberianBranchofRussianAcademy cellproliferationusingBRdU-labeling,andonmigrationandinvasionusingthe
ofSciences xcelligencesystem.Theeffectsofthecombinationtreatmentonvasculartumour
growthwerestudiedinC57BL/6miceinoculatedwithsEnd.2cells.Thesecretionof
Funding:RussianFoundationforFundamentalResearchgrant
VEGF,plateletderivedgrowthfactor(PDGF)andbasicfibroblastgrowthfactor(bFGF)
Disclosure:Allauthorshavedeclarednoconflictsofinterest. weremeasuredemployingELISA.
Results:ILKknockdownwithsiRNAandanti-VEGFtreatmentwithDMH4resultedin
amorepronounceddecreaseincellsurvival,proliferationandmigrationwhen
2P NovelcKITkinaseinhibitor,BPRCKJ001,asanadvanced comparedtotheindividualtreatments,evenfollowingVEGFinduction.The
therapeuticcandidateforGIST combinationtreatmentwasalsomorepotentininhibitingangiogenesisinvitro.
WesternblotanalysisrevealedthesuppressionofAktphosphorylation.Also,results
H-Y.Shiao1,H-J.Tsai2,W-H.Lin1,T-A.Tsu1,T-K.Yeh1,C-T.Chen1, revealedadecreaseintheexpressionofHIF1-aandnitricoxide(NO),aswellasa
W-T.Jiaang1 decreaseinproangiogenicfactors,namely,VEGF,PDGFandbFGF.Invivo,therewasa
1InstituteofBiotechnologyandPharmaceuticalResearch,NationalHealth significantreductionintumordiameterinvasculartumor-bearingmicetreatedwith
ResearchInstitutes,MiaoliCounty,Taiwan,2NationalInstituteofCancer Cpd22,aninhibitorofILKandDMH4(n¼6pergroup;P<0.05).
Research,NationalHealthResearchInstitutes,MiaoliCounty,Taiwan Immunohistochemicalevaluationrevealedareductioninmicrovesseldensityintreated
mice.
Conclusions:Therefore,thecombinationapproachmaybeusefulintheelaborationof
Background:Duringthepastdecade,first-lineuseofimatinibhasbenefitedGIST antiangiogenictherapyinvasculartumors,furtherstudiesarewarranted.
patients.GISTpatientsdevelopimatinib-resistanceduetosecondarymutationincKIT Legalentityresponsibleforthestudy:PeaceMabeta
after20-24monthsofdrugtreatment.Althoughthe2ndlinedrugssuchas,sunitinibis Funding:NationalResearchFoundation;UniversityofPretoria
effective,activationloopmutationsquicklyovercametheirpotentinhibitoryeffects.
Disclosure:Allauthorshavedeclarednoconflictsofinterest.
Moreover,thesedrugshavenumerouspotentialside-effects.Evenwiththenewly
launchedsorafenibandnilotinibforadvancedGIST,thelongtermclinicaloutcomewas
stillnotverypromisingforGISTpatients,duetotherapiddevelopmentofdrug
resistanceoncKIT.
VCEuropeanSocietyforMedicalOncology2016.PublishedbyOxfordUniversityPressonbehalfoftheEuropeanSocietyforMedicalOncology.
Allrightsreserved.Forpermissions,pleaseemail:[email protected].
abstracts
AnnalsofOncology
4P IGF-IR,butnotEGFR,regulatesDNAdamageresponseinHeLa 6P Quinazolineclubbeds-triazinederivativesasVEGFR2kinase
cellsfollowingirradiation inhibitor:Design,synthesis,docking,antiproliferativeand
antiangiogenicactivityoncancer-inducedchickembryo
M.Nishagowri,A.Kaida,M.Miura
OralRadiationOncology,TokyoMedicalandDentalUniversity,Tokyo,Japan A.Verma1,P.Pathak1,P.K.Shukla1,V.Kumar1,A.Kumar2,A.K.Singh3
1PharmaceuticalSciences,SamHigginbottomInstituteofAgriculture,
Technology&Sciences(SHIATS),Allahabad,India,2PharmaceuticalSciences,
Background:TherolesofreceptortyrosinekinasesinDNAdamageresponse(DDR) S.V.SubhartiUniversity,Meerut,India,3Clinical,ESIC,Delhi,India
arestilllargelyunknown.Inthisstudy,weexaminedthepossibleinvolvementof
insulin-likegrowthfactorIreceptor(IGF-IR)andepidermalgrowthfactorreceptor
(EGFR)intheDNAdamageresponse(DDR)followingirradiation. Background:Angiogenesisisafundamentalandcomplexprocessofendothelialcells,
Methods:HeLacellsexpressingthefluorescenceubiquitination-basedcellcycle pericytesandresponsibleforexecutingnormalphysiologicalresponseslikewound
indicator(Fucci)probes(HeLa-Fuccicells)wereusedinthisstudy.KineticsoftheFucci healing,embryonicdevelopmentandboneremodellingetc.JudahFolkmanand
fluorescenceweredetectedbyFACSandtime-lapseimaging.NVP-AEW541, colleaguesestablishedtheconceptofangiogenicinhibitionintumourgrowth.The
TyrphostinAG1478,LY294002,PD98059,NU7026wereusedasspecificinhibitorsfor epidermalgrowthfactor(EGF)receptor(EGFR)andvascularendothelialgrowthfactor
IGF-IR,EGFR,PI3-K,MEK,andDNA-PKcs,respectively.PhosphorylationofERK1/2 (VEGF)pathwaysplayanimportantroleinthegrowth,metastaticpotentialoftumours
andAktwasdetectedbywesternblotting.Doublestrandbreaks(DSBs)weredetected andtheirinhibitionisaprimetargetforvarioustherapeuticagentsincluding
byimmunofluorescencestainingfor53BP1.CellswereirradiatedusinganRX-650 quinazolinebasedcompoundsbecauseitrepresentsthemostvalidatedsignalling
CabinetX-radiatorsystem(Faxitron). pathway.Consideringthatwehavedevelopedquinazolineclubbed1,3,5-s-triazine
derivatives(QCTD)asapotentialinhibitorofVEGFR2kinaseforanti-canceractivity.
Results:ToinvestigatethepossibleinvolvementofEGFRandIGF-IRinG2arrest,
FACSanalysisandtime-lapseimagingofFuccifluorescencewereperformedusing Methods:Designingof(QCTD)wasdoneonthebasisofmolecularfieldmappingand
specificinhibitors.ResultsshowedthatinhibitionofIGF-IR,butnotthatofEGFR, alignmentstudieswithstandardangiogenicinhibitorvandetanib.Furtherdocking
prolongedG2arrest,whichwasirrespectiveofcellcyclephasesatirradiation,i.e.,red studieswereperformedbyAutodock4.2formostpromisingsimilardesigned
(G1phase)orgreen(S/G2phases)phaseintheFuccisystem.Similarly,onlyinhibition derivativesandallscreened(QCTD)weredevelopedviacost-effectivesyntheticroute.
ofIGF-IRdecreasedtheDSBrepairactivity.Hereafter,furtheranalysiswasfocusedon Thesynthesizedderivativeswereevaluatedfortheirin-vitroanti-canceractivityonfour
IGF-IR-associatedevents.WenextattemptedtoidentifytheresponsibleIGF-IR- differentcelllineHeLa(HumanCervicalCarcinoma),MCF-7(BreastCarcinoma),HL-
downstreamsignalingpathways.IrradiationphosphorylatedbothAktandERK; 60(Humanpromyelocyticleukemia)andHepG2(HumanHepatocellularcarcinoma)
however,inhibitionofIGF-IRabrogatedactivationofonlyAkt.Moreover,inhibitionof andandalsoin-ovoangiogenicinhibitionwasperformedonchickembryo.
PI3-K/Akt,butnotthatofMEK/ERK,prolongedG2arrest,whichmimickedthatof Results:Allthedesignedderivativesexploredmorethan50%similarpatternoffield
IGF-IR.InhibitionofDNA-PKcs,amajorfactorofnon-homologousendjoining andatomicarrangement.Thiourea(8b),chloranilino(8d),hrdrazicarboxamide(8j)and
(NHEJ),alsoprolongedG2arrest. methylamino(8m)substitutedderivativesselectedfordockingcalculationsdueto
Conclusions:WeconcludethatirradiationislikelytopreferentiallyactivatetheIGF- highersimilarityvalue.Dockingstudiesrevealedsignificantresultlikestandarddrug
IR/PI3-K/AktsignalingpathwayinHeLa-Fuccicells,whichmayenhanceDSBrepair, vandetanibonproteinVEGFR2kinase(PDBID:3EWH).IC50reportclearlymarked
eventuallycontributingtoreductionofG2arrestintheDDRfollowingirradiation. thatderivativeshavesignificantantiproliferativeactionagainstwideverityofcancercell
lineandin-ovoresultexploredthatderivativesarenon-toxictothenormalcells.
Legalentityresponsibleforthestudy:TokyoMedicalandDentalUniversity
Conclusions:Wehavedevelopedanovelclassofanticanceragents.
Funding:TokyoMedicalandDentalUniversity,MEXTJapan
Legalentityresponsibleforthestudy:N/A
Disclosure:Allauthorshavedeclarednoconflictsofinterest.
Funding:N/A
Disclosure:Allauthorshavedeclarednoconflictsofinterest.
5P Targeteddegradationofanaplasticlymphomakinasebytarget
degraducerinnon-smallcelllungcancer
7P Selenium-enrichedpolysacchridegreenteaextractaltersthe
J.Y.Hwang,C-H.Park,D.H.Lee,C.H.Kang,C.O.Lee,J.D.Ha earlystagehepatocellularcarcinomabyangiogenesishypoxia
Bio&DrugDiscoveryDivision,KoreaResearchInstituteofChemical andmetastaticinhibition
Technology,Daejeon,RepublicofKorea
V.Kumar1,P.C.Bhatt2,F.Anwar3,A.Verma1
1PharmaceuticalSciences,SamHigginbottomInstituteofAgriculture,
Background:Recently,anewandpowerfultechnology,called“proteolysistargeting Technology&Sciences(SHIATS),Allahabad,India,2Pharmacy,Jamiaham-
chimeras”(PROTAC),hasbeenhighlightedinthedrugdiscoveryarea.Treatmentof dard,NewDelhi,India,3Biochemistry,KingAbdulazizUniversity,Jeddah,Saudi
PROTACmolecule,whichcontainsaligandforthetargetedprotein,aligandforE3 Arabia
ubiquitinligasebinding,andalinkerforconnectionoftwoligands,successfullyinduced
targetedproteindegradation,therebyinhibitingcancergrowthininvivoanimalmodel
study.Anaplasticlymphomakinase(ALK)genefusedtovariouspartnergenesare Background:Targetingvariouspathwaysduringprogressionandexpansionof
observedin3–7%ofnon-smallcelllungcancer(NSCLC)inhumans.Theconstitutively hepatocellularcarcinoma(HCC)isonepromisingstrategytocontrolthecomplications
activatedALKfusionsplayanessentialroleincancergrowthandsurvival.Inthisstudy oflivercancer.Thepresentinvestigationtargetedthepotentialeffectofselenium-
weaimedtoidentifynovelALKtargetdegraders(TDs)byapplyingPROTAC enrichedgreenteapolysaccharidesonHOX,hypoxia-inducedfactor,Vascular
technology. EndotheliumGrowthFactor(VEGF),matrixmetalloproteinase(MMP-2andMMP-9),
Methods:LDK-378(ceritinib)asanALKligandandVHLorCRBNasanE3ubiquitin alphafetoprotein(ALF)andCD31indiethylnitrosamineinducedHCCrats.
ligasewereselected.Hydroxyprolineanalogs(HP-7)andpomalidomidewereusedfor Methods:Theextractwasrichinuronicacid(3.2%),carbohydrate(91.2%)and4.5lg/g
VHLandCRBNE3ligaseligands,respectively.AllTDswereevaluatedinenzymatic- ofseleniumtorepresentSCP.Thisextractwasevaluatedforapoptosismechanism
andcell-basedassays.ALKdegradationbyTDswereconfirmedbywesternblottingin againstHCCcelllinesviz.,Hep-G2andHuH-7.Invivostudy,canbereadas:Normal;
SU-DHL-1celllines.Invivoantitumoractivitieswereevaluatedinxenograftmouse NCþSCP(20mg/kg);DENtreated;DENþSCP(20mg/kg).Thetreatmentwas
modelwithH3122celllines. initiatedaweekbeforetheDENadministrationandwascarriedfor22weeks.HCCvia
Results:AseriesofTDsweresynthesizedwithvariouslinkers.TheTDsshowedanti- DENisknownforsignificantalterationinbiochemical,inflammatory,antioxidant
ALKactivitiesinbothenzymaticandcell-basedassays.TheTDsexhibitedALK parametersandliverhistopathology.FurthermorewealsoestimatedtheHOX,HIF,
degradationthroughubiquitination-proteasomeprocessincells.Finally,theTDscould VEGF,MMP-2andMMP-9,ALFandCD31parameters.
inhibittumorgrowthinxenograftstudywithH3122cells. Results:InvitrostudiesconfirmedtheinhibitionofthegrowthofHep-G2andHuH-7
Conclusions:TheseresultssuggestthattheALK-TDs,inducingALKdegradation, cellsinadose-dependentmannerviascavengingthecellatG2phaseofcells.Celldeath
representsapromisingstrategyforthetreatmentofALK-drivenNSCLC. wasconfirmedviaenhancedcaspase3,9activityandBax/Bcl2ratio,suggestingthe
effectonthec-caspasepathwayonapoptosis.Theanimalstudiesconfirmthealteration
Legalentityresponsibleforthestudy:JongYeonHwang
inbiochemical,antioxidantandinflammatorymarkers.Furthertosubstantiateour
Funding:KoreaResearchInstituteofChemicalTechnology claimSCPalsoinhibitedtheproteinelevationofHIF-1a,VEGF,MMP-2,9andCD31
Disclosure:Allauthorshavedeclarednoconflictsofinterest. comparedwithDENcontrolgrouprats.Thealterationintheseparameterswas
sufficienttoconfirmthereductionofangiogenesis,hypoxiaandmetastasisandproved
thepotentialeffectofSCPatearlyexpansionstageofdisease.
Conclusions:Collectively,wecanconcludethatselenium-enrichedpolysaccharidesof
greenteareducedtheprogressionandexpansionofhepatocellularcarcinomavia
multiplemechanisms.
Legalentityresponsibleforthestudy:N/A
ix2|abstracts Volume27|Supplement9|December2016