1.  2013 Genentech USA, Inc. All rights reserved. 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.  2013 Genentech USA, Inc. All rights reserved. 2 Driver mutations can be classified into cell signaling pathways 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. PI3K Akt PTEN FOXO NF1 Ras Proliferation Survival Translation EGFR ERBB2MET PDGFR  Activated oncogenes CDK2NA MDM2 MDM4 TP53 SenescenceApoptosis CDKN2ACDKN2BCDKN2C CDK4CDK6CCND2 Rb1 G1/S progression p53 signaling altered in 87% RTK/Ras/PI3K signaling altered in 88% Rb signaling altered in 78% The commonly implicated pathways leading to growth advantage in glioblastoma multiforme (GBM). Reference: The Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455:1061-1068. Notes

3.  2013 Genentech USA, Inc. All rights reserved. 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 CD8+ T cell MHC I TCR HSPPC-96–antigen Resected tumor APC CD91 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 Clin Oncol. 2013;10:14-26. 3

4.  2013 Genentech USA, Inc. All rights reserved. Therapies that target the epigenome Histone deacetylase (HDAC) reduces the expression of genes associated with cell-cycle regulation HAT  Proliferative signaling  Proliferation SMI  Proliferation Ac HDAC Ac=acetylation; SMI=small-molecule inhibitor; HAT=histone acetylases. Azad N, et al. Nat Rev Clin Oncol. 2013;10:256-266. 4

5.  2013 Genentech USA, Inc. All rights reserved. alkylating agent Unmethylated MGMT promoter MGMT DNA repair Cell survival Biomarkers in malignant glioma: MGMT methylation MGMT=O 6 -methylguanine-DNAmethyltransferase. 5

6.  2013 Genentech USA, Inc. All rights reserved. Methylated MGMT promoter Cell death Alkylating agent Biomarkers in malignant glioma: MGMT methylation MGMT=O 6 -methylguanine-DNAmethyltransferase. 6