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.

BIO00020782001

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

PT

EN

FOXO

NF1

Ras

ProliferationSurvival

Translation

EGFR ERBB2 METPDGFR

Activated oncogenes

CDK2NA

MDM2

MDM4

TP53

Senescence Apoptosis

CDKN2A CDKN2B CDKN2C

CDK4 CDK6CCND2

Rb1

G1/S progression

p53 signalingaltered in 87%

RTK/Ras/PI3K signalingaltered in 88%

Rb signalingaltered 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

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

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

Proliferativesignaling

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

2013 Genentech USA, Inc. All rights reserved.

alkylating agent

Unmethylated MGMT promoter

MGMT

DNA repairCell survival

Biomarkers in malignant glioma: MGMT methylation

MGMT=O6-methylguanine-DNAmethyltransferase. 5

2013 Genentech USA, Inc. All rights reserved.

Methylated MGMT promoter

Cell death

Alkylating agent

Biomarkers in malignant glioma: MGMT methylation

MGMT=O6-methylguanine-DNAmethyltransferase.6