Ciblage Thérapeutique de TGF-betaEric Raymond

Chef de Service d’Oncologie Médicale@ Groupe Hospitalier Paris Saint-Joseph

Paris 75014 - eraymond@hpsj.fr

Cellular&MolecularComponentsoftheHepatocellularCarcinomaMicroenvironment

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

CharacteristicsofHepatocellularCarcinomaMicroenvironment

• Likelytovaryaccordingtothetypeoftumorcarcinogenesis– Alcohol– ViralhepatitisB/Cinducedinflammation– NASH– Others

• Likelytobeinfluencedbyfocalhypoxia– Tumorangiogenesisbeinggenuineorinducedbysorafenib– Inductionofmesenchymal differentiation– Inductionoflacticacidmetabolism– Facilitatetheoccurrencesofspecificoncogenicmutations

• Associatedwithlocalimmunosuppression– InhibitionofT-cellfunctions(PD1/PDL1,CTLA4)

‘Epigenetic’changesmaybefocalaccountingfortumorheterogeneityanddriftoccurringovertimefacilitatingresistancetosingleagenttherapy,pledgingforcombinations

HCC is a highly vascular tumor sensitive to antiangiogenic therapy

SorafenibremainstheonlydrugavailableforadvancedHCC

Llovet JM et al, N Engl J Med 2008

Baseline D23 Sorafenib

SFAIVRE– Beaujon– 019-D-M

CONFIDENTIALGERCOR– BAYERCollaboration

Valérie Paradis,BJN2014

BIOSHARE:DecipheringresistancemechanismsatearlystagesofHCC

JournalofHepatology2011vol.54j1073–1078

EMT

HCCxenografts treatedwithsorafenib shownecrosis,reducedcancercellproliferationandincreasedvimentin expression

Riveiro MEetal,ILCA2011

EMT

TGFbeta

MET

VariousformsofEMTcanberecognizedinHCC

CXCR4

• >30TGFbmembers (TGFb1-3,activins,NODAL,BMP,GDF,AMH)

NeuzilletC.,Pharmacol.Ther.(2015)WakefieldLM.,Nat.Rev.Cancer(2013)

CanonicalandNon-CanonicalTGFb Pathway

TGF-betasignalingincarcinogenesisofHCC

TGF-binhibitionstrategies.ExamplesofTGF-bpathwayinhibitorsandtheiruseinanticancerstrategies.Underlined

moleculeshavereachedphaseIIclinicaldevelopment

Armand de Gramont, Sandrine Faivre & Eric Raymond (2016): NovelTGF-β inhibitors ready for prime time in onco-immunology, OncoImmunology 2017

Summaryofthemainclinicalinterventionsandresults

Armand de Gramont, Sandrine Faivre & Eric Raymond (2016): NovelTGF-β inhibitors ready for prime time in onco-immunology, OncoImmunology 2017

Galunisertib:TGF-βRIInhibitorinHepatocellularCarcinoma

↑ proliferation

↑ invasion/metastasis

Role of TGF-β Signaling in advanced HCCRole of Modulation in E-cadherin, AFP and T Regulatory Cells

↑ sE-cadherin

↑ T regulatory cells

EMT

AFP

LY2157299

↓ E-cadherin

MIGRATION/PROGRESSION

Abbreviations: AFP, alpha-fetoprotein; EMT, Epithelial-mesenchymal transition; sE-cadherin, soluble E-cadherin; TGF-β1, transforming growth factor-beta 1.

LY2157299 monohydrate target plasma exposures: 3 -10.96 mg*h/L

Adapted from Neuzillet, et al. Oncotarget 2013 [Epub ahead of print]

LY2157299 yields potent anti-invasive properties in invasive SK-HEP1, SK-Suni and SK-Sora cell lines

LY2157299displaysanti-invasiveeffectsininvadingcelllines

SK-HEP1

contro

l

10µM LY21

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* p=0.04

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SK-S

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ora

Matrigel invasion OptiCell invasion in fibroblasts-embedded collagen

Serova M et al, ILCA 2013: P-005

TumoralExplant Slicing

Control

DrugA

DrugB

Cultureanddrugtesting

O2

CO2

O2/CO2/T°monitor

Evaluation of Drugs in Ex Vivo Organotypic Culture Assays From SurgicalSpecimens of Human Hepatocellular Carcinoma: Studying the Tumor Cells inTheir Genuine Stroma

BySerovaetal,Oncotarget2015

Exvivo ProliferationControl TGFb inh.

Apoptosis

P-SMAD2/3(PDbiomarker)

(13pts)

(13pts)

(11pts)

TGFbRI InhibitionInducedbyGalunisertibinHumanHepatocellularCarcinomaExplants

BySerovaetal,Oncotarget2015

A Phase 2 Study of a Second Line Galunisertib in Patients With Advanced Hepatocellular Carcinoma

StudyDesignforPartAandPartB

ScreeningPatients with

Child Pugh A or B7 Hepatocarcinoma

who progress Under sorafenib

Galunisertib160 mg/day

Galunisertib300 mg/day

RANDOMIZE

Galunisertib300 mg/day

Part AAFP ≥1.5 ULN

Part BAFP <1.5 ULN

Abbreviation: ULN, upper limit of normal.

CourtesyofFaivreS.etal.Pres.ASCOGI2014andASCO2016

Pharmacodynamic BiomarkersBest Serum TGF-β1 Response

21

53% had TGF-β1 reduction >20%18 (72%) of 25 AFP responders had a

TGF-β1 reduction of >20%

Abbreviations: AFP, alpha-fetoprotein; TGF-β1, transforming growth factor-beta 1.TGF- β1 normal values: 1.7 ng/mL; TGF- β1 values in patients with cancer: 2.66 ng/mL.

Baseline Serum TGF-β1160 mg/d

(N=37)300 mg/d

(N=72)Total

(N=109)

Median (range), ng/mL 3.28(1.62-9.72)

3.66(0.23-37.3)

3.50(0.23-37.3)

Pharmacodynamic BiomarkersBest Serum E-cadherin Response

22

43% had E-cadherin reduction of >20%9 (36%) of 25 AFP responders

had a E-cadherin reduction of >20%

Abbreviation: AFP, alpha-fetoprotein.E-cadherin normal values: 1.5-4.9 mg/mL.

Baseline Serum E-cadherin160 mg/d

(N=37)300 mg/d

(N=69)Total

(N=106)

Median (range), ng/mL 6.05(1.92-17.0)

6.39(1.49-21.5)

6.38(1.49-21.5)

Galunisertib(TGFbRIInhibitor)inPatientsWithHepatocellularCarcinoma

n/N (%) MedianAFP responders 25/103 (24%) 21.4 moAFP non-responders 78/103 (76%) 6.8 mo

Overall survival

AFPresponders=patientswhodecreasedcirculatingAFPlevelsby>20%

AFPnonresponders

AFPresponders

CourtesyofFaivreS.etal.Pres.ASCOGI2014andASCO2016

Part A AFP ≥1.5 ULN

Part B AFP <1.5 ULN

GalunisertibinCombinationWithSorafenibInvivotransgenic C57B16/ASB-Bmice model

At 12weeks

Randomization N = 32

Transgenic C57Bl6/ASV-B Mice; age 8 weeks

Placebo N = 8

Sorafenib + galunisertib

N = 8

Echo-Doppler Every 4 weeks

Sorafenib (30 mg.kg-1)

N = 8

Galunisertib (100 mg.kg-1)

N = 8

Rijeras-Raballanetal.Unpublisheddata

ArmanddeGramontunpublished

PD-L1ExpressioninHepatocellularCarcinoma

Tumorboundary

CD3

PD-L1

CombinationwithPD-L1inhibitors

T-cells

Cancercells

Invivotransgenic C57B16/ASB-Bmice model

PD1/PDL1Inhibitors

CDK4/CDK6inhibitors

PI3K/mTOR inhibitors

Antiangiogenics

TGFbRIInhibitors

PotentialfordevelopmentofcombinationsusinginhibitorsofTGF-betasignaling

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Conclusions• TGF-betasignalingplaysanimportantroleinthemaintenanceofpro-carcinogenictumormicroenvironment

• InhibitionofTGF-betasignalingisshowingpromisingantitumoractivityinhighgradegliomas,pancreatictumorsandhepatocellularcarcinomas

• InhibitionofTGF-betamaypotentiatetheeffectsofotherdrugsmodulatingtumormicroenvironmentincombinationstrials

Thanksforyourattention

EricRaymondChefdeServiced’Oncologie Médicale

@GroupeHospitalierParisSaint-JosephParis 75014- eraymond@hpsj.fr

38thEORTC-PAMMWinterMeeting16th– 18thMarch,Split,Croatia