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Bobby Hodges, Elizabeth Ross, Natalie Simak, Keith Solvang and Eliot Vildaver.

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Presentation on theme: "Bobby Hodges, Elizabeth Ross, Natalie Simak, Keith Solvang and Eliot Vildaver."— Presentation transcript:

1 Bobby Hodges, Elizabeth Ross, Natalie Simak, Keith Solvang and Eliot Vildaver

2 Diseased Genome Hospital blogs.usask.ca/medical_education/archive/ElksRehabFront%2520Door.jpg

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6 What Is Lung Cancer? Types Risks PredispositionMutations EGFR Other proteins Angiogenesis VEGF Your Treatment Plan

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9 NON SMALL CELL  Squamous cell carcinoma  Adenocarcinoma  Large-cell carcinoma SMALL CELL  Bronchi  Grows rapidly  Spreads quickly 38.JPG Lynch et al., (2004)

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11  This year approximately 200,000 people will be diagnosed with lung cancer  NSCLC accounts for 80% of all lung cancers

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13 While there is no known cure as of right now, there ARE options! Imatinib Gefinitib Cisplatin

14 CisplatinImatinib Gefitinib EGF ERBB2 EGFR Nucleus P Protein Cascade

15 P P EGF ERBB2 EGFR PI3K AKT P P MET P VEGF-A CisplatinImatinib Gefitinib Nucleus Protein Cascade PDGFR Protein Cascade

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17  Compact structures of DNA  Contains thousands of genes Centromere Chromatid Genes

18  Single variation in nucleotide base pairs  Alleles are a result of SNPs within gene sequence  SNP’s are the basis for lung cancer susceptibility

19  Variation across genomes  Genotype cases along with controls  Find roles that genes play in disease  Large sample sizes

20 Centromere p-arm q-arm 6 Regions Away Region 5q6 5

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22 Nicotine binds and stimulates acetylcholine ion channel-linked in neurons

23 (Hung et al., 2008)

24 (Thorgeirson et al., 2008)

25 Cancerous Growth

26 (McKay et al., 2008)

27 P P EGF ERBB2 EGFR PI3K AKT P P MET P VEGF-A CisplatinImatinib Gefitinib Nucleus Protein Cascade PDGFR Protein Cascade

28 How Do Cells Proliferate?

29 EGFR P EGF Proliferation Survival Apoptosis ERBB2 Nucleus EGFR P Protein Cascade ERBB2

30 How Can This Lead to Cancer?

31 ERBB2 EGFR Nucleus Proliferation P Protein Cascade

32 (Chen et al., 2006)

33 EGFR ATPTKI ATP binding cleft on the kinase Tyrosine Kinase domain

34 (Chen et al., 2006)

35 What About the Proteins in the Signaling Pathway?

36 (Pedersen et al., 2005)

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38 (Chen et al., 2006)

39 P P EGF ERBB2 EGFR PI3K AKT P P MET P VEGF-A CisplatinImatinib Gefitinib Nucleus Protein Cascade PDGFR Protein Cascade

40 What Are the Roles of Proteins Associated with Lung Cancer?

41 Recap Nucleus N-terminus C-terminus P Serine P Threonine Tyrosine P Leucine Lysine Alanine

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43 ERBB2 P PI3KSH2 Nucleus P Protein Cascade Change in Gene Expression

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45 (Rikova et al. 2007)

46 Green and Blue circles =Proteins involved in cascade Red lines = Interactions Red circles =EGFR Receptor (Jones et al. 2006)

47 No. protein receptors Affinity Threshold (nM) Affinity Threshold (nM) Affinity Threshold (nM)

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49 (Rikova et al. 2007)

50 Chart configured from Table1 of Rikova et al A mount of overphosphorylated protein in samples

51 (Engelman et al., 2007)

52 P P EGF ERBB2 EGFR PI3K AKT P P MET P VEGF-A CisplatinImatinib Gefitinib Nucleus Protein Cascade PDGFR Protein Cascade

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55 VEGF-A VEGFR Angiogenesis Tumors PDGF-β PDGFR-β

56 P85-α PIP 2 P P PTEN P PIP 3 P P P P110-α PI3K AKT SH2 P P Endothelial Cell

57 AKT P P P BAD MDM2 mTOR Growth, Translation Apoptosis p53 P Nucleus

58 Cancer Cell Proto-Oncogene Oncogene

59 (Chen et al., 2009)

60 Giemsa-Stained Cells

61 P85-α PIP 2 P P PTEN P PIP 3 P P P P110-α PI3K AKT SH2 P P VEGF-A VEGFR FLJ10540 Endothelial Cell

62 Binds to ATP binding site of many enzymes: p-PDGFR-β Inhibitor Reduced IFP, Hypoxia Decreased VEGF Expression

63 Normal Tumor

64 (Vlahovic et al. 2007)

65 Vlahovic et al. 2007

66 Imatinib

67 P P EGF ERBB2 EGFR PI3K AKT P P MET P VEGF-A CisplatinImatinib Gefitinib Protein Cascade PDGFR Protein Cascade Nucleus

68 Dr. Vildaver Imatinib Dr. Ross Gefinitib

69 (Rosenberg et al., 1969)

70 Cisplatin Nucleus Simple Diffusion Pt NH 3 GG P73 C-Abl Cell Cycle Arrest & Apoptosis P53 HMG1 ? ?

71 nucleus Pt Transporter protein Transporter protein Pt (Hall et al., 2007)

72 crosslink nucleus Pt NH 3 Cell Cycle Arrest & Apoptosis G G 1,2-intrastrand d(GpG)adduct (Ohndorf et al., 1999)

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74 Pt-DNA Adduct Apoptosis HMGB P73P53 (Stross et al., 2002)

75 (Ohndorf et al., 1999) * Nucleotides crosslinked Bold- nucleotides contacted by the protein

76 (Ohndorf et al., 1999)

77 Cisplatin Nucleus ? Simple Diffusion Pt NH 3 GG P73 C-Abl Cell Cycle Arrest & Apoptosis P53 HMG1 ? ?

78 tyrosine kinase mismatch repair protein cisplatin homologue of p53 Tumor suppresor (Gong et al., 1999)

79 P53 knockout= less sensitive to CDDP, survived better than wild type in lower concentrations of CDDP MLH1-/- & Abl= less sensitive to CDDP, survived better than wild type in lower concentrations of CDDP (Gong et al., 1999)

80 Cisplatin Nucleus Simple Diffusion Pt NH 3 GG P73 Cell Cycle Arrest & Apoptosis P53 HMG1 ATM Transporter Proteins C-Abl P

81 CisplatinImatinib Gefitinib EGF ERBB2 EGFR Nucleus P Protein Cascade

82 P P EGF ERBB2 EGFR PI3K AKT P P MET P VEGF-A CisplatinImatinib Gefitinib Nucleus Protein Cascade PDGFR Protein Cascade

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84  New plasma membrane proteins have unique mechanisms and effects on NSCLC  Gefitinib effectively inhibits particular EGFR mutants  SiRNA could be used as a possible treatment for various mutated proteins

85  How does cisplatin enter the nucleus?  Roles and mechanisms behind the various mutated proteins involved in lung cancer  New drugs, secondary mutations

86 Professor Sleiter Schmooing yeast!!!

87 Dr. DebBurman

88 Mike Fiske

89 Abid MR, Guo S, Minami T, Spokes KC, Ueki K, et al. (2004) Vascular endothelial growth factor activates PI3K/Akt/forkhead signaling in endothelial cells. Arterioscler Thromb Vasc Biol 24: Agami, R., Blandino, G., Oren, M., and Shaul, Y. (1999). Interaction of c-Abl and p73alpha and their collaboration to induce apoptosis. Nature 399, Alberg AJ, Ford JG, Samet JM; American College of Chest Physicins. Epidemiology of lung cancer: ACCP evidence-based clinical practice guidelines (2 nd edition). Chest. 2007; 132:29S-55S. Alberts, B., Bray, D., Hopkin, K., Johnson, A., Lewis, J., Raff, M., Roberts, K., and Walter, P Essential Cell Biology. Garland Science. New York, pp740. Chanock, Stephen J., Hunter, David J When the smoke clears. Nature. 452: Chen, C.H., Lai, J.M., Chou, T.Y., Chen, C.Y., Su, L.J., Lee, Y.C., Cheng, T.S., Hong, Y.R., Chou, C.K., Whang-Peng, J., Wu, Y.C., and Huang, C.Y. (2009). VEGFA upregulates FLJ10540 and modulates migration and invasion of lung cancer via PI3K/AKT pathway. PLoS ONE 4, e5052. Chen, Y.R., Fu, Y.N., Lin, C.H., Yang, S.T., Hu, S.F., Chen, Y.T., Tsai, S.F., and Huang, S.F. (2006). Distinctive activation patterns in constitutively active and gefitinib-sensitive EGFR mutants. Oncogene 25, Engelman, J.A., Janne, P.A., Mermel, C., Pearlberg, J., Mukohara, T., Fleet, C., Cichowski, K., Johnson, B.E., and Cantley, L.C. (2005). ErbB-3 mediates phosphoinositide 3- kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines. Proc. Natl. Acad. Sci. U. S. A. 102, Ferrara, N. and Kerbel, R.S. (2005). Angiogenesis as a therapeutic target. Nature 438, 967. Franks, L.M. and Teich, N. (1986). Introduction to the Cellular and Molecular Biology of Cancer (New York:Oxford University Press). Gao, B., Lee, S.M., and Fang, D. (2006). The tyrosine kinase c-Abl protects c-Jun from ubiquitination-mediated degradation in T cells. J. Biol. Chem. 281, Hall, M.D., Okabe, M., Shen, D.W., Liang, X.J., and Gottesman, M.M. (2008). The role of cellular accumulation in determining sensitivity to platinum-based chemotherapy. Annu. Rev. Pharmacol. Toxicol. 48, Helotera, H. and Alitalo, K. (2007). The VEGF Family, the Inside Story. Cell 130: Hung, Rayjean J. et al A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature. 452: Huang, J.C., Zamble, D.B., Reardon, J.T., Lippard, S.J., and Sancar, A. (1994). HMG-domain proteins specifically inhibit the repair of the major DNA adduct of the anticancer drug cisplatin by human excision nuclease. Proc. Natl. Acad. Sci. U. S. A. 91, Jemal A, Siegel R, Ward E, Hao Y, Xu J, et al. (2008) Cancer statistics, CA Cancer J Clin 58:

90 Johnson DH, Blot WJ, Carbone DP, et al. Cancer of the lung_Non-small cell lung cancer and small cell lung cancer. In: Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKena WG. Clinical Oncology. 4th ed. Philadelphia, Pa: Churchill Livingstone Elsevier: 2008: chap 76. Jones, R.B., Gordus, A., Krall, J.A., and MacBeath, G. (2006). A quantitative protein interaction network for the ErbB receptors using protein microarrays. Nature 439, Kwak, E.L., Sordella, R., Bell, D.W., Godin-Heymann, N., Okimoto, R.A., Brannigan, B.W., Harris, P.L., Driscoll, D.R., Fidias, P., Lynch, T.J. et al. (2005). Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc. Natl. Acad. Sci. U. S. A. 102, McKay, James D. et al Lung cancer susceptibility locus at 5p Nature Genetics. 40(12): Moyer JD, Barbacci EG, Iwata KK, Arnold L, Boman B, et al. (2006) Induction of apoptosis and cell cycle arrest by CP-358,774, and inhibitor of epidermal growth factor receptor tyrosine kinase. Cancer Res 57: Ohndorf, U., Rould, M., He, Q., Pabo, C., Lippard (1999). Basis for recognition of cisplatin-modified DNA by high-mobility-group proteins. Nature. 399: Pedersen, M.W., Pedersen, N., Ottesen, L.H., and Poulsen, H.S. (2005). Differential response to gefitinib of cells expressing normal EGFR and the mutant EGFRvIII. Br. J. Cancer 93, Pietras K, Ostman A, Sjoquist M, Buchdunger E, Reed RK, Heldin CH, Rubin K (2001) Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors. Cancer Res 61: Poklar, N., Pilch, D.S., Lippard, S.J., Redding, E.A., Dunham, S.U., and Breslauer, K.J. (1996). Influence of cisplatin intrastrand crosslinking on the conformation, thermal stability, and energetics of a 20-mer DNA duplex. Proc.Natl. Acad. Sci. U. S. A. 93, Rikova, K., Guo, A., Zeng, Q., Possemato, A., Yu, J., Haack, H., Nardone, J., Lee, K., Reeves, C., Li, Y. et al. (2007). Global Survey of Phosphotyrosine Signaling Identifies Oncogenic Kinases in Lung Cancer. Cell 131, Ruddon, R.W. (2007). Cancer Biology: Fourth Edition (New York: Oxford University Press). Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH (2002) Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346: Shilo, B., Yarden, Y. (2007). Snap Shot: EGFR Signaling Pathway. Cell.131, 1018e1-1018e2. Stros, M., Ozaki, T., Bacikova, A., Kageyama, H., and Nakagawara, A. (2002). HMGB1 and HMGB2 cell-specifically down-regulate the p53- and p73-dependent sequence-specific transactivation from the human Bax gene promoter. J. Biol.Chem. 277, Thorgeirson, Thorgeir E. et al A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature. 452: Vlahovic G, Rabbani ZN, Herndon II JE, Dewhirst MW, Vujaskovic Z (2006) Treatment with Imatinib in NSCLC is associated with decrease of phosphorylated PDGFR-beta and VEGF expression, decrease in interstitial fluid pressure and improvement of oxygenation. Br J Cancer 95: 1013– Yarden, Y., and Sliwkowski, M.X. (2001). Untangling the ErbB signalling network. Nat. Rev. Mol. Cell Biol. 2, Yuan, Z.M., Shioya, H., Ishiko, T., Sun, X., Gu, J., Huang, Y.Y., Lu, H., Kharbanda, S., Weichselbaum, R., and Kufe, D. (1999). p73 is regulated by tyrosine kinase c-Abl in the apoptotic response to DNA damage. Nature 399, Yun, C.H., Mengwasser, K.E., Toms, A.V., Woo, M.S., Greulich, H., Wong, K.K., Meyerson, M., and Eck, M.J. (2008). The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc. Natl. Acad. Sci. U. S. A. 105,


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