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Disclosure/Disclaimer. The Molecular Basis of Gliomas slide presentation is not an independent educational program, and no CME credits will be provided. This program is not intended to promote any cancer agent or class approved by the FDA/EMA or currently under clinical development.

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  1. Disclosure/Disclaimer • The Molecular Basis of Gliomas slide presentation is not an independent educational program, and no CME credits will be provided. • This program is not intended to promote any cancer agent or class approved by the FDA/EMA or currently under clinical development. • The contents of this slide presentation are owned solely by Genentech; any unauthorized uses are prohibited. • This program is presented on behalf of Genentech and the information presented is consistent with FDA guidelines. • The following slides are selected samples from a complete presentation. They are for educational purposes only. BIO0002078200 1

  2. Driver mutations can be classified into cell signaling pathways Notes p53 signalingaltered in 87% RTK/Ras/PI3K signalingaltered in 88% Rb signalingaltered in 78% The commonly implicated pathways leading to growth advantage in glioblastomamultiforme (GBM). Reference: The Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455:1061-1068. ERBB2 MET Activated oncogenes EGFR PDGFR CDKN2A CDKN2B CDKN2C CDK2NA CDK4 CCND2 CDK6 Ras PI3K PTEN MDM2 NF1 MDM4 Akt Rb1 TP53 ProliferationSurvivalTranslation FOXO G1/S progression Senescence Apoptosis CDKN2A=cyclin-dependent kinase inhibitor 2A; MDM2=MDM2 oncogene; MDM4=Mdm4 p53 binding protein homolog; TP53=tumor protein p53; EGFR=epidermal growth factor receptor; ERBB2=v-erb-b2 erythroblastic leukemia viral oncogene homolog 2; PDGFRα=platelet derived growth factor alpha; Ras=rat sarcoma; NF1=neurofibromin 1; PI3K=phosphatidylinositol 3-kinase; PTEN=phosphatase and tensin homolog; FOXO=forkhead box O1; CDKN2B=cyclin-dependent kinase inhibitor 2B; CDKN2C=cyclin-dependent kinase inhibitor 2C; CDK4=cyclin-dependent kinase 4 CCND2=cyclin D2; CDK6=cyclin-dependent kinase 6; Rb1=retinoblastoma 1. Vogelstein B, et al. Science. 2013;339:1546-1558. The Cancer Genome Atlas Research Network. Nature. 2008;455:1061-1068. 2

  3. Tumor-specific immunotherapy via HSP-conjugated vaccine Glioma antigens bound to HSPs elicit specific immune responses • Following immunization, HSPPC-96–antigen complexes are internalized by APCs via CD91 receptor • APCs then present to CD8+ T cells on MHC class I Resected tumor CD91 APC HSPPC-96–antigen MHC I TCR CD8+ T cell HSP=heat shock protein; APCs=antigen-presenting cells; MHC=major histocompatibility complex; PFS=progression-free survival; TCR=T-cell receptor. Crane CA, et al. Clin Cancer Res. 2013;19:205-214. Abbas AK, Lichtman AH, eds. Basic Immunology: Functions and Disorders of the Immune System. 2nd ed. Philadelphia, PA: Saunders; 2004:177-192. Tanaka S, et al. Nat Rev ClinOncol. 2013;10:14-26. 3

  4. Therapies that target the epigenome • Histone deacetylase (HDAC) reduces the expression of genes associated with cell-cycle regulation Ac SMI HAT HDAC  Proliferativesignaling  Proliferation  Proliferation Ac=acetylation; SMI=small-molecule inhibitor; HAT=histone acetylases. Azad N, et al. Nat Rev ClinOncol. 2013;10:256-266. 4

  5. Biomarkers in malignant glioma: MGMTmethylation Unmethylated MGMT promoter alkylating agent MGMT DNA repair Cell survival MGMT=O6-methylguanine-DNAmethyltransferase. 5

  6. Biomarkers in malignant glioma: MGMTmethylation Methylated MGMT promoter Alkylating agent Cell death MGMT=O6-methylguanine-DNAmethyltransferase. 6

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