ESOC 2016: Bromodomain inhibitors - Bet what are BETs
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Bromodomain inhibitors Eric Raymond MD, PhD Chair of Medical Oncology @ Groupe Hospitalier Paris Saint-Joseph - France [email protected]
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Transcript of ESOC 2016: Bromodomain inhibitors - Bet what are BETs
BromodomaininhibitorsEricRaymondMD,PhD
ChairofMedicalOncology@Groupe Hospitalier ParisSaint-Joseph- France
Disclosures– Oncoethyx– Pfizer– Novartis– EliLilly– Ipsen
CancerMayArisefromAberrantEpigeneticChromatinRegulation
NatureReviewsMolecularCellBiology 16, 258–264 (2015)
Histoneacetyltransferases(HATs)andmethyltransferases
Histonedeacetylases(HDAC)anddemethylases
Bromodomaincontainingproteins
key oncogenes and anti-apoptotic proteins
BromodomainProteinsAreUnpackingDNA&HelpActivatingRNAPolymeraseforInitiationofGeneTranscription
NatureReviewsMolecularCellBiology 16, 258–264 (2015)
NuclearProteininTestis
NUTmidlinecarcinoma(NMC)ischaracterizedbyasinglet(15;19)(q14;p13.1)chromosomaltranslocation
PositiveTranscriptionElongationFactorB
FurthertoBromodomainReaderActivation,InitiationofRNASynthesisMayProceed
BromodomainProteinsCo-regulateNetworksofTranscriptionalActivationandRepression
NatRevCancer12:465-477,2012
Cancerproliferation
Cancermicroenvironment
Viral-inducedCancerinitiation
Structure&RelationshipsAmongBromodomain-Proteins&Inhibitors
NatRevCancer12:465-477,2012
PredictedDruggability andBindingofSmallMoleculestoBromodomains
BRDcomplexes
NatRevCancer12:465-477,2012
BromodomainInhibitorsinClinicalTrials
Ther Adv Hematol,Vol.6(3)128–141,2015
PotentialTumorsThatCanBeSensitivetoBromodomainInhibitors
• NUT-midlinecarcinoma• MYCdependenttumors
– Multiplemyeloma– Non-HodgkinandBurkitt lymphoma– Medulloblastoma
• Acutemyeloidleukemia• Hepatocellularcarcinoma• Pancreaticcancer• Castration-resistantprostatecancer• Triplenegativebreastcancer• ALK-positivenon-smallcelllungcancer
JQ1hasbeenaleadforpreclinicalexperimentsbutwasnotsuitableforclinicaldevelopment
BromodomainInhibitionLeadstoGeneExpressionChangesThatMayAffectHematologicalMalignancies
Ther Adv Hematol,Vol.6(3)128–141,2015
OTX-015AloneandinCombinationinB-cellLymphoma
EugenioGaudio etal.AACR2014
CombinationsofOTX-015inLeukemiaCells
LucileAstorgues-Xerri etal.AACR2014
OTX015inNon-Small-CellLungCancerCellsBearingtheFusionProteinEML4–ALK
c-myc n-myc
RamiroVazquez etal.AACR2014
OTX-015inNeuroblastomaModels
JohannesH.Schulte etal.,AACR2014
First-in-HumanPhaseIDataofOTX-015• Humanswithlymphomaoracuteleukemiagivenupto60mg/day
oralOTX015experiencedthrombocytopenia asadose-limitingtoxicity
• Nauseaandfatiguewerealsoobserved
• NUT-midlinecarcinoma(3patients):– Rapidtumorregressionandsymptomaticimprovement(18&19
months)intwopatients– Athirdpatientstabilizedanddemonstratedmetabolicresponse
• Hematologicalmalignancies(28patients):– Twopatientswithacutemyelogenousleukemia(AML)demonstrateda
completeresponse– Twopatientswithlymphomahadapartialresponse
• Hormonerefractoryprostatecancer– SeveralpatientsdemonstratedsignificantPSAdecreases
AdvancesinCancerResearch,131,2016,Pages21–58
PharmacokineticDataofOralOTX-015inPatientsWithHematologicalMalignancies
ElodieOdoreetal.AACR2014
OTX-015inNUTMidlineCarcinomaClinicalproofofconcept
NMCaredefinedbyrearrangementsoftheNUT,akaNUTM1,geneonchromosome15.q14
MostcommonlytherearrangementisatranslocationbetweenBRD4(chr. 19p13.1)andNUT,formingtheBRD4–NUT-fusionin75–80%ofcases
NMCisoneofthemostaggressivesolidtumorknown,havingamediansurvivalof6.7months
Baseline OTX-015
AdvancesinCancerResearch,131,2016,Pages21–58
NUTstandsforNuclearProteininTestis
ResistancetoBromodomainInhibitors
• ActivationoftheWnt/β-cateninpathway inleukemiacells– TheresistancetoBETinhibitionoccurreddespitecontinuedinhibitionofBRD4targets
– BRD4-dependenceisbypassedandWnt/β-catovertakestoactivateMYC
• ConstitutivephosphorylationofBRD4intriplenegativebreastcancercells
• NMC?
AdvancesinCancerResearch,131,2016,Pages21–58
PotentialofBromodomainInhibitorsinCancerTherapy
NUTmidlinecarcinoma
BRD4–NUT-fusion
Drivingoncogene
Maydependofthecontext
MYC-dependenttumorsLymphoma/leukemia
Hormoneresistantprostatecancer
TriplenegativebreastcancerALKlungcarcinoma
Regulationoftranscription
Synergywithmanycytotoxicandtargeted
agents
Combinations
Conclusions• BromodomainfamilyofproteinsareinvolvedinreadingofacetylatedDNAandfacilitatetheinitiationoftranscriptionofmajoroncogenessuchasc-myc
• Bromodomaininhibitorsarenovelclassofmoleculeswithpotentialactivityinawildrangeoftumortypeseitheraloneorincombination
• PhaseItrialswithbromodomain inhibitorsshowedproofofconceptactivityinBRD-activatedtumorssuchasNUTmidlinecarcinoma,leukemia,andlymphoma
Thanksforyourattention
EricRaymondMD,PhDChairofMedicalOncology
@GroupeHospitalierParisSaint-JosephFrance
