MET/HGFrelevancefortargetedtherapymalignancies

EricRaymondMD,PhDChairofMedicalOncology

@Groupe Hospitalier ParisSaint-Joseph- Franceeraymond@hpsj.fr

Disclosures– Pfizer– Novartis– EliLilly– Ipsen– Oncoethyx

Cellular&MolecularComponentsofCarcinomaMicroenvironments

EndothelialcellsPericytesVEGFR-PDGFR

Tcells(CD4-Treg)CD4:PD1-CTLA4-CD28Treg:CD73-CD39

DendriticcellsPDL1-PD1-MSHII-CD80/86

TumorassociatedmacrophagesCXCR4-TGFβR

TumorcellsTGFβR-MET-PDL1

FibroblastsFGFR

TGFβHGFFGF19IL8IL10

SDF1/CXCL12

MET/HGFHistoricalMilestonesMET:MesenchymaltoEpithelialTransitionfactor/HGF:HepatocyteGrowthFactor

1984 1991 1994 1997

Identificationofthemet oncogeneinachemicallytransformedhumanosteosarcomacellline(Cooper)

c-metmapstochromosomebands7q21-31

c-met proto-oncogenewasdetectedonthecellsurfaceandclassifiedasagrowthfactorreceptorofthetyrosinekinasefamily

c-met proto-oncogeneactsasatransmembranetyrosinekinasereceptorforasingleligand,HGF(Bottaro)

AnautocrineloopofanotherwiseunalteredHGF/c-METpairconfersoncogenicproperties(Bellusci)

Identificationofgermlinemutationsofthec-met proto-oncogeneinhereditarypapillaryrenalcarcinomaandestablishmentofageneticlinkbetweenc-METandcancer(Schmidt)

1982

A peptidegrowthfactor,structurallyrelatedtoplasminogen,wasisolatedandcharacterizedasanewsubstanceresponsibleforliverregenerationintheserumofpartiallyhepatectomized rats(Michalopoulos,Nakamura,Michalopoulos,Thaler)

Ascatterfactor wasshowntodisruptintercellularjunctionsofepithelialcells,stimulatetheirmigrationinaparacrinemannerandpromoteaninvasivephenotype(Stoker,Weidner)

1985

Hepatotropin &hepatopoietin wassubsequentlypurifiedfromtheplasmaofpatientswithfulminanthepaticfailure,fromratplatelets,normalhumanplasma,rabbitserum,andratliver(Gohda,Nakamura,Zarnegar

DesignationofHGFasamitogen,motogen andmorphogen)(Rubin,Montesano,Matsumoto)

AdaptedfromPetrSzturz etal,inpress2016

StructuralDeterminantsofMET/HGF

MET

AdaptedfromPetrSzturz etal,inpress2016&ShinyaMizuno& ToshikazuNakamura Int.J.Mol.Sci.2013

RelevantDockingSitesinCancer

Adapted from Shinya Mizuno & Toshikazu Nakamura Int.J.Mol.Sci.2013

CellularEffectsofHGFinVariousCellularComponentsoftheTumorMicroenvironment

Adapted from Shinya Mizuno & Toshikazu Nakamura Int.J.Mol.Sci.2013

HGF/METCooperateswithHER1-3toDevelopAggressivePhenotypes

AdaptedfromPetrSzturz etal,inpress2016

Therapy-InducedHGFSecretionProtectsAgainstApoptosisandConfersResistancetoAnticancerDrugs

Hypoxia- Necrosis

SunitinibSorafenib

Adapted from Shinya Mizuno & Toshikazu Nakamura Int.J.Mol.Sci.2013

Senino B,etal.Cancer Discovery2012&Faris JE,etal.ASCO 2014

NCT01466036- Cabozantinib pNET &Carcinoids

DualVEGFR/C-METinhibitorsmaycounteractEMTactivationdevelopedunderanti-VEGF/VEGFRinhibitors

c-METDysfunctionsCommonlyObservedinCarcinomas

47%

26%

23%

4%

mRNAoverexpression

Proteinoverexpression

Geneamplification

Mutation

Chronicinflammation

Fibrosis

Localimmunosuppression

GenuineHypoxia

Treatmentinducedhypoxia(embolization,anti-angiogenic)

Exposuretochemotherapyandradiotherapy

Randomgenemutation

IdentificationofSelectivec-Met&EGFRInhibitorsinaVichemCompoundLibraryina3DTissueCulture-BasedHigh-Content

ScreeningPlatform(prostatecancercells)

http://ocello.nl/development-3d-tissue-culture-based-high-content-screening-platform-uses-phenotypic-profiling-discriminate-selective-inhibitors-receptor-tyrosine-kinases/

CurrentMET/HGFInhibitors

Tepotinib

DARPin MP0250

AdaptedfromSPeters&A.A.Adjei NatureReviewsClinicalOncology 9, 314-326 (2012)

PotentialofMET/HGFInhibitorsinCancerTherapy

Reducedangiogenesis

Potentiationofanti-angiogenic

drugs

Tumorangiogenesis

Directinhibitionofcancercellinvasionandmetastasis

RestoreofDNAdamageinductionofapoptosis

CounteractresistancetoEGFR/HER2-3inhibitors

Tumorcellsignaling

Restorethelocalinhibitionof

dendriticcells&T-lymphocytes

Maypotentiatetheeffectsofcheckpointinhibitors

Immunestroma

ç Combinationsè

Conclusions• Variouscomponentsoftumormicroenvironmentcouldbeusedastargetstocontroltumorgrowthandprogressioninhumancarcinoma

• MET/HGFinhibitorsappearaspromisingoptions fortumoraggressivenessbyinhibitinginvasion&metastasesandrestoresensitivitytoDNA-damagingagentsincludingradiotherapy,HER-inhibitors,andantiangiogenics

• CombinationsofMET/HGFwiththerapiesknowntoinduceepithelial-to-mesenchymal-transitionofferpromisesinsustainingcontroloftumorprogression

Thanksforyourattention

EricRaymondMD,PhDChairofMedicalOncology

@GroupeHospitalierParisSaint-JosephFrance

eraymond@hpsj.fr