Bobby Hodges, Elizabeth Ross, Natalie Simak, Keith Solvang and
Eliot Vildaver Slide 2 Diseased Genome Hospital http://
blogs.usask.ca/medical_education/archive/ElksRehabFront%2520Door.jpg
Slide 3
http://1.bp.blogspot.com/_HI2mCx5P3H0/SLlEQoHj8AI/AAAAAAAAA8Q/My7tf78TNc8/s320/hospital-bed-786282.jpg
Slide 4 http://img.quamut.com/chart/9471/02_healthy_sick_x-ray.jpg
Slide 5
http://www.cardiothoracicsurgery.org/content/2/1/16/figure/F1?highres=y
Slide 6 What Is Lung Cancer? Types Risks PredispositionMutations
EGFR Other proteins Angiogenesis VEGF Your Treatment Plan
http://www.freefoto.com/images/21/16/21_16_2---Single-Carriageway-Road_web.jpg
Slide 7
http://www.odec.ca/projects/2005/thog5n0/public_html/Tumour.gif
Slide 8 http://www.icowman.com/uploadfiles/2007072409225175.jpg
Slide 9 NON SMALL CELL Squamous cell carcinoma Adenocarcinoma
Large-cell carcinoma SMALL CELL Bronchi Grows rapidly Spreads
quickly
http://images.google.com/imgres?imgurl=http://www.dkimages.com/discover/previews/852/202230
38.JPG
http://images.google.com/imgres?imgurl=http://upload.wikimedia.org/
Lynch et al., (2004) Slide 10
http://www.taconichills.k12.ny.us/webquests/noncomdisease/lungcancerpic.jpg
Slide 11 This year approximately 200,000 people will be diagnosed
with lung cancer NSCLC accounts for 80% of all lung cancers
http://www.cdc.gov/cancer/lung/statistics/
http://seo2.0.onreact.com/wp-content/uploads/2008/09/you-re-not-alone.jpg
Slide 12
http://medicineworld.org/cancer/lung/http://images.google.com/
Slide 13 While there is no known cure as of right now, there ARE
options! http://dspace.mit.edu Imatinib Gefinitib Cisplatin
http://dspace.mit.edu Slide 14 CisplatinImatinib Gefitinib EGF
ERBB2 EGFR Nucleus P Protein Cascade Slide 15 P P EGF ERBB2 EGFR
PI3K AKT P P MET P VEGF-A CisplatinImatinib Gefitinib Nucleus
Protein Cascade PDGFR Protein Cascade Slide 16
http://rosenblumtv.files.wordpress.com http://www.pharmgkb.org
http://academic.evergreen.edu Slide 17 Compact structures of DNA
Contains thousands of genes Centromere Chromatid Genes
http://staff.jccc.net/PDECELL/celldivision/chromosome1.gif Slide 18
Single variation in nucleotide base pairs Alleles are a result of
SNPs within gene sequence SNPs are the basis for lung cancer
susceptibility
http://www.dnalandmarks.com/english/pictures/what_are_snps.jpg
Slide 19 Variation across genomes Genotype cases along with
controls Find roles that genes play in disease Large sample sizes
http://www.blog.speculist.com/archives/dna2two Slide 20 Centromere
p-arm q-arm 6 Regions Away Region 5q6 5 http://images.google.com/
Slide 21 http://upload.wikimedia.org/ Slide 22 Nicotine binds and
stimulates acetylcholine ion channel-linked in neurons
http://www.jyi.org/articleimages/88/originals/img0.jpg Slide 23
(Hung et al., 2008) Slide 24 (Thorgeirson et al., 2008) Slide 25
Cancerous Growth http://images.google.com/i Slide 26 (McKay et al.,
2008) Slide 27 P P EGF ERBB2 EGFR PI3K AKT P P MET P VEGF-A
CisplatinImatinib Gefitinib Nucleus Protein Cascade PDGFR Protein
Cascade Slide 28 How Do Cells Proliferate? Slide 29 EGFR P EGF
Proliferation Survival Apoptosis ERBB2 Nucleus EGFR P Protein
Cascade ERBB2 Slide 30 How Can This Lead to Cancer? Slide 31 ERBB2
EGFR Nucleus Proliferation P Protein Cascade Slide 32 (Chen et al.,
2006) Slide 33 EGFR ATPTKI ATP binding cleft on the kinase Tyrosine
Kinase domain Slide 34 (Chen et al., 2006) Slide 35 What About the
Proteins in the Signaling Pathway? Slide 36 (Pedersen et al., 2005)
Slide 37 Slide 38 (Chen et al., 2006) Slide 39 P P EGF ERBB2 EGFR
PI3K AKT P P MET P VEGF-A CisplatinImatinib Gefitinib Nucleus
Protein Cascade PDGFR Protein Cascade Slide 40 What Are the Roles
of Proteins Associated with Lung Cancer?
http://www.taconichills.k12.ny.us/webquests/noncomdisease/lungcancerpic.jpg
Slide 41 Recap Nucleus N-terminus C-terminus P Serine P Threonine
Tyrosine P Leucine Lysine Alanine Slide 42 Slide 43 ERBB2 P PI3KSH2
Nucleus P Protein Cascade Change in Gene Expression Slide 44 Slide
45 (Rikova et al. 2007) Slide 46 Green and Blue circles =Proteins
involved in cascade Red lines = Interactions Red circles =EGFR
Receptor (Jones et al. 2006) Slide 47 No. protein receptors
Affinity Threshold (nM) Affinity Threshold (nM) Affinity Threshold
(nM) Slide 48 http://en.wikipedia.org/wiki/Proteins Slide 49
(Rikova et al. 2007) Slide 50 Chart configured from Table1 of
Rikova et al. 2007 A mount of overphosphorylated protein in samples
Slide 51 (Engelman et al., 2007) Slide 52 P P EGF ERBB2 EGFR PI3K
AKT P P MET P VEGF-A CisplatinImatinib Gefitinib Nucleus Protein
Cascade PDGFR Protein Cascade Slide 53
http://www.taconichills.k12.ny.us/webquests/noncomdisease/lungcancerpic.jpg
Slide 54
http://www.researchvegf.com/researchvegf/multimedia/index.m#type-slides
Slide 55 VEGF-A VEGFR Angiogenesis Tumors PDGF- PDGFR- Slide 56
P85- PIP 2 P P PTEN P PIP 3 P P P P110- PI3K AKT SH2 P P
Endothelial Cell Slide 57 AKT P P P BAD MDM2 mTOR Growth,
Translation Apoptosis p53 P Nucleus Slide 58 Cancer Cell
Proto-Oncogene Oncogene Slide 59 (Chen et al., 2009) Slide 60
Giemsa-Stained Cells Slide 61 P85- PIP 2 P P PTEN P PIP 3 P P P
P110- PI3K AKT SH2 P P VEGF-A VEGFR FLJ10540 Endothelial Cell Slide
62
http://www.medicinescomplete.com/mc/martindale/2007/images/MRT9229C001.gif
Binds to ATP binding site of many enzymes: p-PDGFR- Inhibitor
Reduced IFP, Hypoxia Decreased VEGF Expression Slide 63
http://www.medscape.com/pi/editorial/clinupdates/2000/583/art-tu02.fig04.jpg
http://www.nature.com/nm/journal/v7/n9/images/nm0901-987-F1.gif
Normal Tumor Slide 64 (Vlahovic et al. 2007) Slide 65 Vlahovic et
al. 2007 Slide 66
http://onctalk.com/wp-content/uploads/2008/01/angiogenesis-summary.jpg
Imatinib Slide 67 P P EGF ERBB2 EGFR PI3K AKT P P MET P VEGF-A
CisplatinImatinib Gefitinib Protein Cascade PDGFR Protein Cascade
Nucleus Slide 68 Dr. Vildaver Imatinib Dr. Ross Gefinitib Slide 69
(Rosenberg et al., 1969) Slide 70 Cisplatin Nucleus Simple
Diffusion Pt NH 3 GG P73 C-Abl Cell Cycle Arrest & Apoptosis
P53 HMG1 ? ? Slide 71 nucleus Pt Transporter protein Transporter
protein Pt (Hall et al., 2007) Slide 72 crosslink nucleus Pt NH 3
Cell Cycle Arrest & Apoptosis G G 1,2-intrastrand d(GpG)adduct
(Ohndorf et al., 1999) Slide 73
http://www.unc.edu/~shantanu/images/bkstcg_aacr07.png Slide 74
Pt-DNA Adduct Apoptosis HMGB P73P53 (Stross et al., 2002) Slide 75
(Ohndorf et al., 1999) * Nucleotides crosslinked Bold- nucleotides
contacted by the protein Slide 76 (Ohndorf et al., 1999) Slide 77
Cisplatin Nucleus ? Simple Diffusion Pt NH 3 GG P73 C-Abl Cell
Cycle Arrest & Apoptosis P53 HMG1 ? ? Slide 78 tyrosine kinase
mismatch repair protein cisplatin homologue of p53 Tumor suppresor
(Gong et al., 1999) Slide 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) Slide
80 Cisplatin Nucleus Simple Diffusion Pt NH 3 GG P73 Cell Cycle
Arrest & Apoptosis P53 HMG1 ATM Transporter Proteins C-Abl P
Slide 81 CisplatinImatinib Gefitinib EGF ERBB2 EGFR Nucleus P
Protein Cascade Slide 82 P P EGF ERBB2 EGFR PI3K AKT P P MET P
VEGF-A CisplatinImatinib Gefitinib Nucleus Protein Cascade PDGFR
Protein Cascade Slide 83 http://immunodefence.com/ii/gefitinib.gif
http://www.themesotheliomalibrary.com/cisplatin.jpg
http://www.specialityformulations.com/pcat-gifs/products-small/imatinib.jpg
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effects on NSCLC Gefitinib effectively inhibits particular EGFR
mutants SiRNA could be used as a possible treatment for various
mutated proteins Slide 85 How does cisplatin enter the nucleus?
Roles and mechanisms behind the various mutated proteins involved
in lung cancer New drugs, secondary mutations Slide 86 Professor
Sleiter Schmooing yeast!!! Slide 87 Dr. DebBurman Slide 88 Mike
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