 2013 Genentech USA, Inc. All rights reserved. Disclosure/Disclaimer The Molecular Basis of Colorectal Cancer 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. BIO

 2013 Genentech USA, Inc. MBoC Program 2 Angiogenesis is a function of multiple signals from multiple cell types Pericyte PDGF, TGFβ Paracrine factors VEGF, Ang-2, bFGF Endothelial cell Tumor cell O2 O2 Nutrients PDGF=platelet-derived growth factor; TGFβ=transforming growth factor beta; VEGF=vascular endothelial growth factor; Ang-2=angiopoietin; bFGF=basic fibroblast growth factor. Angiogenesis is a vital process in the progression of cancer from small, localized neoplasms to larger and potentially metastatic tumors. Angiogenic vessels deliver oxygen, nutrients, and survival factors to cancer cells. 1,2 References: 1.Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23: Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003;3: Notes

 2013 Genentech USA, Inc. MBoC Program 3 The EGFR homodimer and heterodimer activate different signaling pathways EGFR=epidermal growth factor receptor; HER3=human epidermal growth factor receptor-3; Grb2=growth factor receptor-bound protein 2; Sos=son of sevenless; Ras=rat sarcoma; PI3K=phosphatidylinositol 3-kinase; PDK1=phosphoinositide-dependent kinase-1; Raf=rapidly accelerating fibrosarcoma; MEK=mitogen-activated protein kinase kinase; MAPK=mitogen-activated protein kinase; mTOR=mammalian target of rapamycin; BAD=Bcl-2–associated death promoter; NFκB=nuclear factor kappa-light-chain enhancer of activated B cells; GSK3β=glycogen synthase kinase 3 beta. Yarden Y, et al. Nat Rev Mol Cell Biol. 2001;2: Sergina NV, et al. Nature. 2007;445: Servidei T, et al. Int J Cancer. 2008;123: Buck E, et al. Mol Cancer Ther. 2006;5: Kim HH, et al. J Biol Chem. 1994;40: AKT PDK1 PI3K Cyclin D1 p27 BAD GSK3ß NFκB mTOR Cell-cycle control ↓ Apoptosis ↑ Survival EGFR HER3 ProliferationAngiogenesis EGFR Sos Grb2ShcRas Raf MEK MAPK Epidermal growth factor receptor (EGFR) activation drives many pathways leading to activation of targeted genes within the nucleus that can lead to cell proliferation. 1-3 References: 1.Zhang L, Bewick M, Lafrenie RM. EGFR and ErbB2 differentially regulate Raf-1 translocation and activation. Lab Invest. 2002;82: Fang JY, Richardson BC. The MAPK signalling pathways and colorectal cancer. Lancet Oncol. 2005;6: Sergina NV, Rausch M, Wang D, et al. Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature. 2007;445: Notes

 2013 Genentech USA, Inc. MBoC Program Prognostic and predictive: MSI in CRC MSI=microsatellite instability. Vilar E, Gruber SB. Nat Rev Clin Oncol. 2010;7: Flanking sequence Microsatellite sequence CA repeat Flanking sequence Microsatellites are tandem repeats of nucleotides, usually cytosine and adenine Different lengths of tandem repeats between 2 loci notes MSI Biomarkers for CRC predisposition Predictive biomarkers for response to chemotherapy 4

 2013 Genentech USA, Inc. MBoC Program 5 5-FU metabolic pathway: Genetic variants can impact response 5-FU DPD FdUMP (active metabolite) TS Tumor DNA synthesis 5-FU=5-fluorouracil; DPD=dihydropyrimidine dehydrogenase deficiency; FdUMP=5-fluorodeoxyuridine monophosphate; TS=thymidylate synthase. Increased TS, increased resistance 5-FU is converted intracellularly to the active metabolite fluorodeoxyuridine monophosphate (FdUMP), leading to cell death by interfering with tumor DNA synthesis. Reference: Longley DB, Harkin P, Johnston PG. 5-Fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003;3: Notes

 2013 Genentech USA, Inc. MBoC Program 6 5-FU metabolic pathway: Genetic variants can impact response 5-FU FdUMP (active metabolite) TS Tumor DNA synthesis DPD 5-FU=5-fluorouracil; DPD=dihydropyrimidine dehydrogenase deficiency; FdUMP=5-fluorodeoxyuridine monophosphate; TS=thymidylate synthase. Decreased DPD, increased toxicity Patients who are deficient in dihydropyrimidine dehydrogenase (DPD) experience profound systemic toxicity to 5-FU due to decreased catabolism and prolonged drug exposure. Reference: Longley DB, Harkin P, Johnston PG. 5-Fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003;3: Notes

 2013 Genentech USA, Inc. MBoC Program 7 5-FU metabolic pathway: Genetic variants can impact response 5-FU DPD FdUMP (active metabolite) TS Tumor DNA synthesis Increased TS, increased resistance 5-FU=5-fluorouracil; DPD=dihydropyrimidine dehydrogenase deficiency; FdUMP=5-fluorodeoxyuridine monophosphate; TS=thymidylate synthase. Increased expression of thymidylate synthase (TS) has been associated with suboptimal response to 5-FU  based chemotherapy. Reference: Longley DB, Harkin P, Johnston PG. 5-Fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003;3: Notes