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.
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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