paediatric gliomas denise sheer
TRANSCRIPT
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
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
Nucleosomalfibre
Corehistones
Linkerhistone
Essen-alCellBiology,Albertsetal,3rdEd.
Muta-onsinHistoneH3.3,ATRX&DAXX
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
Iden-fica-onofbiomarkersImprovedclinicaltrialdesign
Developmentoftargetedtreatment
Dis-nctmolecularsubgroupsinpaediatrichigh-gradeglioma
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
ReceptorTyrosineKinases
ExtracellularSignals
E.H.Raabe, Clin Cancer Res 2011; K.Jacob, Clin Cancer Res 2011
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
ReceptorTyrosineKinases
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
Whydodelaysindiagnosisoccur?
• Symptomsandsignsmimiccommon,lessseriousdisorders• Symptoms&signsareveryvaried
– dependingontheirloca-on– dependingontheageofthechild– theirseveritycanfluctuate
• Childhoodbraintumoursarerela-velyrare– GPswilltypicallyseeonlyone,maybetwo,childhoodbraintumoursintheirwholecareer
Launch:June2011
• Over1.5millionSymptomsCardsdistributed• Extensivemediacampaign• Almost100,000hitsonwebsite• Drama-cimprovementindiagnos-cinterval
DavidWalker:AnewclinicalguidelinefromtheRoyalCollegeofPaediatricsandChildHealthwithana-onalawarenesscampaignacceleratesbraintumordiagnosisinUKchildren—“HeadSmart:BeBrainTumourAware”Neuro-Oncology2015
MeanDiagnos4cInterval: Pre-campaign -14weeks May2013 -6.7weeks