Tumeurs ce re brales de l adolescent et du jeune adulte. L exemple du gliome du tronc (20 mn) Dr Jacques Grill - Institut Gustave Roussy, Villejuif

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1 Tumeurs ce re brales de l adolescent et du jeune adulte L exemple du gliome du tronc (20 mn) Dr Jacques Grill - Institut Gustave Roussy, Villejuif

2 Tumeurs ce re brales de l adolescent et du jeune adulte L exemple des gliomes histone-dépendants Dr Jacques Grill - Gustave Roussy, Villejuif

3 Pediatric malignant gliomas are different from adult malignant gliomas Philippe et al, unpublished High-grade Gliomas - ESO 3

4 Distribution of the principal mutations Schwartzentruber et al, Nature 2012

5 Sturm et al Cancer Cell 2012 Les Tumeurs Gliales 5

6 Mutations are different according to location 01/12/ Sturm et al, Cancer Cell 2012

7 Gene expression differs according to location Glioma re-express an embryonic signature linked with location DIPG MIDLINE THALAMIC HEMISPHERIC Puget et al, PLoS ONE 2012

8 Histone H3 mutations in Gliomas & Epigenetic Reprogramming In cancer context, numerous epigenetic alteration accumulate => Opportunity for reversal of differentiation and reprogramming Histone H3 mutations might be the driver of these changes H3* K27M No H3K27me3 (repressive mark) H3* G34R/V H3K36me3 (activating mark) J Schwartzentruber et al. Nature (2012)

9 Mutation on histone H3.1 is specific to DIPG H3.1 K27M H3.3 G34V/R H3.3 & H3.1 WT 140 pediatric high-grade glioma tumors from Necker (Sanger Sequencing)

10 Age distribution HGG/DIPG with histone H3 mutations Schwartzentruber et al, Nature 2012

11 0 to 1 1 to 2 2 to 3 3 to 4 4 to 5 5 to 6 6 to 7 7 to 8 8 to 9 9 to to to to to to to to to to to to to to to to 25 >25 Age distribution of H3K27M DIPG Castel et al, submitted

12 Age distribution of the DIPG subtypes Castel et al, submitted

13 Taylor et al, Nature Genetics 2014

14 MAY 2013 CANCER DISCOVERY

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18 Critères diagnostiques histologiques Perte de la triméthylation en H3K27 Présence de la mutation H3.3K27M

19 Difficultés diagnostiques Pourcentage de cellules tumorales Cross-Reaction avec les DIPG H3.1

20 Difficultés diagnostiques Tous les 70 gliomes infiltrants du tronc typiques en imagerie ont une perte de la triméthylation en H3K27. Mutations rares = H3F3A(K27I), HIST1H3C (K27M), HIST2H3C (K27M).

21 DIPG cellular phenotype is linked to the type of histone H3 variant mutated at K27 HES VIM - O L I G O HES VIM + A S T R O GUSTAVE ROUSSY

22 H3.1 mutated DIPG show large areas of necrosis H3.3 H3.1 RR of necrosis = 1.75 OR for necrosis = 2.81 (95%CI= ) 22

23 H3.3 mutated DIPG show frequently stripes (p=0.01). 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% H3.3 H3.1 23

24 H3.1 mutated DIPG have a less agressive course than H3.3 mutated ones and a better response to therapy.. Clinical response to RT P= ChiSq test Better Same Or Worse H H Probability Kaplan Meier stratified by Histone H3 Mutation n=53 K27M H3.1, 15 pts K27M H3.3, 38 pts Survival Time in Months Log rank test p= GUSTAVE ROUSSY Castel et al. ISPNO 2014

25 H3.3 mutated DIPG are more prone to metastases than H3.1 mutated DIPG H3.3 H3.1 N=15/31 cases N=0/10 cases Half of the patients with H3.3 mutated tumors died with mets while none with H3.1 mutated tumors did (p<0.01, Fisher exact test). GUSTAVE ROUSSY Castel et al. ISPNO 2014

26 BIOMEDE Thérapie ciblée personnalisée dans les gliomes infiltrants du tronc cérébral

27 EGFR POS PTEN LOSS 1% 3% 30% 10% 3% 10% 30% PDGFRA AMP

28 Les trois cibles majeures sélectionnées EGFR Rarement amp/mut, souvent surexprimé (50%). Cible déjà testée dans les essais précédents. Voie de signalisation mtor Activée par altération génomique dans près de la moitié des DIPG (Taylor et al, Nat Genet 2014)). Perte d expression de PTEN dans plus de 80% des DIPG. PDGFRA PDGFRA amp/mut dans 20% des DIPG. Surexpression/Activation dans les formes proneurales/mutées H3.3.

29 EGFR POS PTEN LOSS R1 R1 R3 R3 R2 R2 No R PDGFRA AMP R1=Erlo/Dasa R2=Ever/Dasa R3=les 3

30 Clinical & Radiological Diagnosis ICF1 for biopsy and biomarkers analysis Uncertain Diagnosis Biopsy Exome sequencing 100X RNAseq profiling Histological Confirmation Biomarkers At relapse Drug Selection At diagnosis ICF2 pour R1,2,3

31 BIOMEDE Destination du matériel biologique NEM271 (H3.1) Diagnostic - H3K27me3 - H3.3K27M Biomarkers - EGFR (IHC) - PTEN (IHC) - PDGFRA (FISH) Génomics - Sequencing H3.3 and H3.1 - WES (+ blood) - RNAseq Avatars

32 Remerciements Sponsors INCA, Etoile de Martin, De fi de Fortune e Collaborateurs Stéphane Pfister (DKFZ), Michelle Monje (Stanford), Pierre Leblond (Lille), Mark Kieran (DFCI), Chris Jones (Royal Marsden), Arne Ostman (Karolinska). Equipe CNRS UMR 8203 David Castel, Marie-Anne Debily, Nathalène Truffaux, Ludivine Le Dret, Estelle Daudigeos, Gaétan Cornilleau, Gille Vassal.