paediatric gliomas denise sheer

MolecularFounda-onsofPaediatricGliomas:ThePlotThickens

Denise Sheer

Overview

1.  Cancerasadiseaseofthegenome2.  Paediatricbraintumours3.  Glioblastoma4.  Low-gradeglioma5. HeadSmart

•  Cancer arises from the accumulation of Genetic aberrations •  Epigenetic aberrations are also present

•  Together, they give rise to altered gene expression

•  Over 500 genes are now known to be involved in cancer

1.Cancerasadiseaseofthegenome

If we know which genes are involved, we can:

•  Have a better understanding of cancer biology

•  Develop diagnostic and prognostic markers

•  Follow the clinical course

•  Develop targeted treatment

Major classes of cancer genes

Gene-caberra-ons

Chromosomedefects

Muta-ons

Low mutation frequency in children’s cancer

Strachan et al. Genetics & Genomics in Medicine (2015)

Epigene-caberra-onsMechanismsforalteringgeneexpressionwithoutaffec6ngtheDNAsequence

Histonetailmodifica-onsDNAmethyla-on

RegulatoryRNA

2.Paediatricbraintumours

•  Leadingcauseofcancer-relateddeathinchildren•  Difficulttotreat

•  Requireinterdisciplinarytherapeu-capproach•  Survivorscanhavelong-termneurological,motor,hormonal,

&cogni-veimpairment

•  Neuropathologymovedfrommorphology-basedapproachtouseofimmunohistochemical&molecularmarkers

•  Biologystar-ngtobeunderstoodfrommolecularstudies

•  Targetedtreatmentsemerging

Grade I Pilocytic astrocytoma Angiocentric glioma Grade II Diffuse astrocytoma Pilomyxoid astrocytoma Pleomorphic xanthoastrocytoma Grade III Anaplastic astrocytoma

Grade IV Glioblastoma

Overviewofpaediatricgliomas

3. Paediatric glioblastoma

•  Highlymalignant,diffuselyinfiltra-ngtumour•  Leadingcauseofcancer-relateddeathinchildren•  2-yearsurvival~12%•  HistologysimilartoadultGBM•  Molecularfounda-onsaredis-nctfromadultGBM

Paediatric GBM Young adult GBM Adult GBM

Adapted from E.H.Raabe et al, Cancer Cell 2012

UPDATED:C.W.Brennanetal(TCGA),Cell2013

TP53

RTK/RAS/PI3K

RB

543glioblastomas

TheCancerGenomeAtlas(TCGA)ResearchNetwork,Nature2008

AdultGBM:Deregula-onofp53,RB,RTK/RAS/PI3Kpathways

Paediatric glioblastoma

Muta-onsinHistoneH3.3,ATRX&DAXX

J.Schwartzentruberetal,Nature2012

(H3.3)

Paediatric glioblastoma

Nucleosomalfibre

Corehistones

Linkerhistone

Essen-alCellBiology,Albertsetal,3rdEd.

Muta-onsinHistoneH3.3,ATRX&DAXX

H3.3

H3.3isenrichedatregulatoryelements,promotersandac-vegenes

TheATRX/DAXXcomplexloadsH3.3ontochroma-n

DAXXH3.3

ATRX

Muta-onsinHistoneH3.3Leadtoalteredgeneexpression

K27M G34R/V

J. Schwartzentruber et al, Nature 2012, L. Bjerke et al, Cancer Research 2013

MYCNGloballossofH3K27m3

Sequestra-onofPolycombEZH2

TP53mut

Adapted from A.Korshunov et al, Acta Neuropathol 2015

Dis-nctmolecularsubgroupsinpaediatrichigh-gradeglioma

Gajjar et al, JCO 2015


Iden-fica-onofbiomarkersImprovedclinicaltrialdesign

Developmentoftargetedtreatment


Pilocytic astrocytoma •  Most common paediatric brain tumour •  Typically in cerebellum or midline along hypothalamic/optic pathways •  Well-circumscribed, non-invasive •  Usually treated with surgery alone •  Activating mutations in the MAPK signalling pathway (and PI3K) Diffuse astrocytoma •  Infiltrating tumours •  Occur throughout the CNS •  Difficult to remove with surgery alone •  Treated with radiation and chemotherapy •  Activating mutations in the MAPK signalling pathway (and PI3K) •  MYB mutations

4.Paediatriclow-gradeglioma

KIAA1549-BRAF

Chr 7 KIAA1549 BRAF

Tandemduplica-on

Forshewetal,J.Pathol2009

BRAFgenefusionsinpilocy-castrocytomas

BRAF7

controlprobe

BRAF

KIAA1549

KIAA1549-BRAF

TransmembranedomainRas-bindingdomainCysteine-richdomainKinasedomainGlycine–richloopAc-va-onsegment

Fusionbreakpoint

T.Forshew et al, J. Pathol 2009; R.G.Tatevossian et al, J. Cell Physiol 2010

KIAA1549-BRAF fusion

BRAFmuta-oninpilocy-canddiffuseastrocytomas

Ras-bindingdomain

Cysteine-richdomain

Kinasedomain

Glycine–richloop

Ac-va-onsegment

V600E

ExtracellularSignals

Activation of the MAPK pathway

BRAF

MEK1/2

ERK1/2

RAS

P

P

Prolifera4on

NF1

ReceptorTyrosineKinases

Activation of the MAPK pathway

BRAF

MEK1/2

ERK1/2

RAS

P

P

Oncogene-InducedSenescence

NF1


ExtracellularSignals

E.H.Raabe, Clin Cancer Res 2011; K.Jacob, Clin Cancer Res 2011

Wholegenomesequencingofpaediatriclow-gradegliomas

J.Zhang et al, Nature Genetics 2013

J.Zhang et al, Nature Genetics 2013

Wholegenomesequencingofpaediatriclow-gradegliomas

KIAA1549-BRAFFAM131-BRAF

FXR1-BRAFBRAF-MACF

SRGAP3-RAF1QKI-RAF1

BRAFv600e

NF1-m

FGFR1-TKDFGFR1-TACC1FGFR1-TACC3QKI-NTRK2NACC2-NTRK2

Zhang et al, Nat Genetics 2013; Jones et al, Nat Genet 2013; Penman et al, Front Oncol 2015

Muta-onsinpaediatriclow-gradegliomas

Vemurafenib Dabrafenib

Sorafenib

Selumetinib

Perifosine

Perifosine MK2206

Rapamycin Everolimus

PI-103

Bevacizumab Sorafenib Erlotinib

VEGF VEGFR EGFR

KIAA1549-BRAFFAM131-BRAF

FXR1-BRAFBRAF-MACF

SRGAP3-RAF1QKI-RAF1

BRAFv600e

NF1-m

FGFR1-TKDFGFR1-TACC1FGFR1-TACC3QKI-NTRK2NACC2-NTRK2

Zhang et al, Nat Genetics 2013; Jones et al, Nat Genet 2013; Penman et al, Front Oncol 2015

Opportuni-esfortargetedtherapy

M.A. Karajannis, Neuro-Oncology 2014

Opportuni-esfortargetedtherapy

NCT01338857

Sorafenib

ACCELERATEDTUMOURGROWTH!

Sorafenibtrial:Acceleratedtumourgrowthduetoinhibi-onofsenescence?

BRAF

MEK1/2

ERK1/2

RAS

P

P

Oncogene-InducedSenescence

NF1


E.H.Raabe, Clin Cancer Res 2011; K.Jacob, Clin Cancer Res 2011

Pilocy-castrocytomashaveup-regula-onofmicroRNAsthattargettheMAPKandNF-kBpathways:

JonesJeyapalanetal,ActaNeuropathCommunica-ons(inpress)

Sorafenibtrial:Acceleratedtumourgrowthduetoinhibi-onofregulatoryfactors?

Cross-talkbetweensignallingpathways:M.C.Mendozaetal,TIBS2011

Sorafenibtrial:Acceleratedtumourgrowthduetopathwaycross-talk?

Gene-c,Epigene-c,Proteinprofiling

Biology DiagnosisSub-classifica-on

PrognosisResponsetotherapy

Newtherapeu-capproaches

Weneedacomprehensiveunderstandingofalltheregulatoryelementstorealisethefullpoten-alforpa-entcare

Thanks to:

AmericanLebaneseSyrianAssociatedChari-es

Dr.ThomasJacques,Ins-tuteofChildHealth/GOSH,UniversityCollegeLondonProf.DavidEllison&Dr.RuthTatevossian,StJudeChildren’sResearchHospital,MemphisUSA

JennieJeyapalan

TaniaCorbeN-Jones JohanAarum WilliamQays

Foster-HallNeilAtam

5. HeadSmart

HeadSmartis a national campaign

in the UK to raise awareness of the

signs and symptoms of brain tumours

in children and young people

amongst the public and health professionals

to reduce diagnosis times,

reducing long-term disabilities and saving lives

Early diagnosis can

improve the outcome –

saving lives and

reducing long-term

disability

The‘pathway’todiagnosisChildrenopenhavemul-plecontactswithhealthprofessionalsbeforediagnosis

Whydodelaysindiagnosisoccur?

•  Symptomsandsignsmimiccommon,lessseriousdisorders•  Symptoms&signsareveryvaried

– dependingontheirloca-on– dependingontheageofthechild–  theirseveritycanfluctuate

•  Childhoodbraintumoursarerela-velyrare– GPswilltypicallyseeonlyone,maybetwo,childhoodbraintumoursintheirwholecareer

Launch:June2011

•  Over1.5millionSymptomsCardsdistributed•  Extensivemediacampaign•  Almost100,000hitsonwebsite•  Drama-cimprovementindiagnos-cinterval

Onlineeduca-onalmaterialsandtraining

www.headsmart.org.uk

DavidWalker:AnewclinicalguidelinefromtheRoyalCollegeofPaediatricsandChildHealthwithana-onalawarenesscampaignacceleratesbraintumordiagnosisinUKchildren—“HeadSmart:BeBrainTumourAware”Neuro-Oncology2015

MeanDiagnos4cInterval: Pre-campaign -14weeks May2013 -6.7weeks

Supportedby:

APartnershipbetween:

Pioneeredby:ProfessorDavidWalker,Noungham

paediatric gliomas denise sheer

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