esmo.org

PRECISION MEDICINE IN NETTargeted drugs: Where are we heading to?

Prof Eric Raymond, MD, PhDGH PARIS SAINT JOSEPH – Franceeraymond@hpsj.fr

185 rue Raymond Losserand – 75014 Paris

DISCLOSURE SLIDEHonoraria and Research Grants:

PfizerIpsenNovartisEli Lilly

u Neuroendocrine tumors are characterized by specific genetic (mutations & epigenetic changes) alterations that primarily concern anti-oncogene

u Mutation-driving activations of the mTOR pathway is thought to be responsible of changes in metabolic fate and proliferation of neuroendocrine tumor cells

u Pancreatic neuroendocrine tumors are also characterized by a strong activation of VEGF/VEGFR-dependent angiogenesis either induced by VHL mutations or a hypoxic microenvironment induced by tumor growth

u Other targets and the immune microenvironment are poorly known but may represent exciting potentials for novel therapeutic approaches

Biological patterns in neuroendocrine tumors

MSLawrence etal. Nature 000,1-5(2013)doi:10.1038/nature12213

Somatic mutation frequencies observed in exomes from 3,083 tumor–normal pairs

Neuroendocrine tumors are diseases characterized by loss of tumor suppressor genes

> 50% unknown somatic mutations or other

abnormalities

TGF-β R1 & R2

SMAD7

AKT1

TGF-α

EGFR

RAS/RAF

MEK/ERK

PI3K

AKT

MEN1

Protein interactome involved in neuroendocrine neoplasm proliferation

Endothelialcell

Tumorcell

PDGFVEGF

Apoptosis

PDGFVEGF

IGFIGF1-RP

HIF-1 HIF-2

SurvivalProliferation

PRas

PAKT

P

Nucleus

MitochondriaMitochondria

P

Nucleus

Angiogenesis:DifferentiationProliferationMigrationTubuleformationApoptosis

PDGF-BB

PI3k

x

P P P

VEGF-AVEGF-C

Paracrine

stimulation

PI3k

S6K1

PmTOR

PAKT

VEGFR-2 VEGFR-3PDGFR-b

Hypoxia

PDGF-BB

PDGFR-b

NucleusP

PI3k

S6K1

PmTOR

PAKT

mTOR

SSR

Somatostatin

Hypoxia

Pericytes

Neuroendocrine

TumorsTumorvessel

permeability

Autocrine

&paracrine

stimulation

Faivre S, et al. Endocrinol Metab Clin N Am 2010;39:811–826

Cellular consequences of genetic and epigenetic changes observed in NETs

Activationofproliferationandlossofcellcyclecontrol

Lossofapoptosis

Increasedinvasiveness&metastases

Changesinmetabolism(Kreb’s cycle)

Hypoxiaandpseudohypoxia

Epigeneticoncogeneactivationrelatedtolossesinanti-oncogenecontrolandchromatinremodeling

Adapted from Joakim Crona and Britt Skogseid; European Journal of Endocrinology (2016) 174, R275–R290

Losses of genetic, proteomic, and epigenetic controls of NET cells yield novel paradigms for clinical interventions

Capdevila J et al. Oncogene advance online publication, 2016

Pharmacological attempts to control tumor growth on major reactivation pathways are likely to be associated with adaptive resistance mechanisms

Adaptive resistance

mechanisms

Cellulardifferentiation

Somatostatin analogues

PRRTSSR

Metabolic pathwayactivation EverolimusmTOR

Hypoxia & pseudohypoxia SunitinibVEGFR

Genetic and epigenetic oncogene reactivation

Immunotherapy

?

Novel antigens

Other microenvironment changes

u Resistance to VEGF/VEGFR and mTOR inhibitors have been evaluated in some preclinical models leading so far to limited clinical applications

u Preclinical data suggest peculiar patterns:u Unlike resistance to chemotherapy, mechanisms leading to lost of sensitivity to

targeted therapy could be at least in part reversible u Resistance to VEGFR inhibitors does not affect sensitivity to mTOR inhibitorsu This offers the opportunity of using sequential therapy with VEGFR and mTOR

inhibitors

Resistance to VEGFR and mTOR inhibitors

1.SuiXetal.CellDeathDis.2013;4:e838.doi:10.1038/cddis.2013.350.2.ZahreddineHetal.FrontPharmacol.2013;4:28.doi:10.3389/fphar.2013.00028.3.BuczekMetal.BiochemBiophysActa. 2014;1845:31-41.4.BergersGetal.NatRevCancer.2008;8(8):592-603.5.Izar Betal.PharmacolRev.2013;65:1351-1395.11

What do we know about resistance to mTOR Inhibitors?

Acquired resistance- Activation of alternative pathways- Mutations in mTORC1/FKPB12- Loss of PP2A function- Stimulation of autophagy (competes with

apoptosis)

12Reprinted with permission from: Tijeras-Raballand et al. Targ Oncol .2012; 7:173-181.

Mechanisms for Overcoming Resistance to mTOR Inhibitors

mTOR,mammaliantargetofrapamycin;mTORCmammaliantargetofrapamycincomplex;IGFR,insulinlikegrowthfactorreceptor;MOA,mechanismofaction.

1. Tijeras-RaballandAetal.TargetOncol.2012;7(3):173-181.2.IzarBetal.PharmacolRev.2013;65:1351-1395. 13

Potentialstrategiestoovercomeresistance1,2

• NovelinhibitorsthatblockbothmTORC1andmTORC2

• CombinationtherapieswithmTOR inhibitorandasecondagentthatblocksupstreamkinases(AKTorPI3K)orreceptors(IGFR)

• mTOR/EGFRdualinhibition(eg,rapamycin/erlotinib)

• SequentialtreatmentwithagentshavingdifferentMOAs

u mTORC1 blockade induces AKT activation by feedback loop, which can be attenuated by IGR blockade induced by SSAs2

u SSAs decrease secretion of IGF-1 ligand, thereby diminishing paracrine/autocrine activation of IGF-1R and its downstream effects (ie, on AKT)3

u Everolimus and SSA might act synergistically to inhibit protein synthesis and decrease angiogenesis4

u However, the addition of pasireotide to everolimus did not improve PFS in pts with progressive pNETs - COOPERATE-2 study [NCT01374451]5

Combinations of mTOR Inhibitors and SSAs1

1. SalazarRetal.Drugs.2011;71(7):841-852.2.O’ReillyKEetal.CancerRes.2006;66(3):1500-1508.3.SusiniCetal.AnnOncol.2006;17:1733-1742.4.BousquetC.

JClinEndocrinol Metab. 2012;97:727-737.5.Kulkeetal.ENETSCongress2015(oralpresentation) 14

Resistance to anti-angiognic agents: Intrinsic (Primary) vs Adaptive (Secondary)

Reprinted with permission from: Bergers G, et al. Nat Rev Cancer. 2008;8:592-603. 15

STRATEGIES TO REVERT RESISTANCE TO ANTIANGIOGENESIS APPROACH

MoserleL,etal.CancerDiscovery 2014

Sequential administration of sunitinib and everolimus may delay substantially progression in well differentiated PNET

Sunitinib37.5 mg/dayre-challenge

Sunitinib 25 mg/day

Sunitinib 37.5 mg/day

ChemotherapyEverolimus

Time from diagnosis of advanced pNET ~7 years, 3 months

63 66 69 72 7548 51 54 57 6033 36 39 42 4518 21 24 27 303 6 9 12 15 84 87 9078 81015

20

25

30

35

40

45

Size

of l

onge

st d

iam

eter

s (m

m)

Evaluations (months)

*

*Performed at 2 months

Senino B,etal.Cancer Discovery 2012;Faris JE,etal.ASCO 2014

NCT01466036Cabozantinib pNET &Carcinoids

Dual VEGFR/C-MET inhibitors may counteract EMT activation developed under anti-VEGF/VEGFR inhibitors

Native & treatment-induced antigen releases in neuroendocrine tumors offer the potential for immunotherapy

AdaptedfromPietroAmeri,DiegoFerone,Neuroendocrinology2011

CD73

Vaccination

Checkpoint inhibitors

Reversing resistance: Future of targeted therapies in neuroendocrine tumors

mTOR inhibitionEverolimus

VEGFR/PDGFR inhibitionSunitinib

Somatostatin analoguesOctreotideLanreotide

PRRT

Primarytargets

mTOR inhibitionOthers

VEGFR/PDGFR inhibitionOthers

Somatostatin analoguesOthers

Analogtargets

TT with checkpoint inhibitors

TT with chemotherapy

TT with PRRT

TT with nanoparticles

Combinations

TGF-beta R1/2 inhibitors

CXCR4 inhibitors

EGFR inhibitors

PI3K/MEK/ERK inhibitors

NOTCH inhibitors

Noveltargets

MET inhibitors

u Resistance to targeted agents in pNET remains poorly understood

u Based on clinical observations, sequential administrations of targeted therapies seem to be able delaying progression

u Understanding mechanisms of NET carcinogenesis may help identifying targets and drugs that can counteract primary and acquired resistance to targeted therapies

Conclusion

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