MET/HGF relevance for targeted therapy malignancies Eric Raymond MD, PhD Chair of Medical Oncology @ Groupe Hospitalier Paris Saint-Joseph - France [email protected]
Feb 08, 2017
MET/HGFrelevancefortargetedtherapymalignancies
EricRaymondMD,PhDChairofMedicalOncology
@Groupe Hospitalier ParisSaint-Joseph- [email protected]
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