Bobby Hodges, Elizabeth Ross, Natalie Simak, Keith Solvang and Eliot Vildaver
http://blogs.usask.ca/medical_education/archive/ElksRehabFront%2520Door.jpg
http://1.bp.blogspot.com/_HI2mCx5P3H0/SLlEQoHj8AI/AAAAAAAAA8Q/My7tf78TNc8/s320/hospital-bed-786282.jpg
http://img.quamut.com/chart/9471/02_healthy_sick_x-ray.jpg
http://www.cardiothoracicsurgery.org/content/2/1/16/figure/F1?highres=y
What Is Lung
Cancer?
•Types
•Risks
Predisposition
Mutations
•EGFR
•Other
proteins
Angiogenesis
•VEGF
http://www.freefoto.com/images/21/16/21_16_2---Single-Carriageway-Road_web.jpg
Your
Treatment Plan
http://www.odec.ca/projects/2005/thog5n0/public_html/Tumour.gif
http://www.icowman.com/uploadfiles/2007072409225175.jpg
http://www.icowman.com/uploadfiles/2007072409225175.jpg
NON SMALL CELL



Squamous cell carcinoma
Adenocarcinoma
Large-cell carcinoma
Lynch et al., (2004)
SMALL CELL



Bronchi
Grows rapidly
Spreads quickly
http://images.google.com/imgres?imgurl=http://upload.wikimedia.org/
http://images.google.com/imgres?imgurl=http://www.dkimages.com/discover/previews/852/202230
38.JPG
http://www.taconichills.k12.ny.us/webquests/noncomdisease/lungcancerpic.jpg

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
http://medicineworld.org/cancer/lung/
http://images.google.com/
While there is no known cure as of right
now, there ARE options!
Imatinib
Gefinitib
Cisplatin
http://dspace.mit.edu
http://dspace.mit.edu
Protein
Cascade
P
Nucleus
P
P
P
Protein
Cascade
AKT
Protein
Cascade
P
Nucleus
http://rosenblumtv.files.wordpress.com
http://www.pharmgkb.org
http://academic.evergreen.edu
Compact structures of
DNA
 Contains thousands of
genes
Chromatid

Centromere
Genes
http://staff.jccc.net/PDECELL/celldivision/chromosome1.gif
Single variation in
nucleotide base pairs
 Alleles are a result of
SNPs within gene
sequence
 SNP’s are the basis for
lung cancer
susceptibility

http://www.dnalandmarks.com/english/pictures/what_are_snps.jpg
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
6 Regions Away
p-arm
Centromere
Region 5q6
q-arm
5
http://images.google.com/
http://upload.wikimedia.org/
http://upload.wikimedia.org/
http://www.jyi.org/articleimages/88/originals/img0.jpg
Nicotine binds and stimulates acetylcholine
ion channel-linked in neurons
(Hung et al., 2008)
(Thorgeirson et al., 2008)
Cancerous Growth
http://images.google.com/i
(McKay et al., 2008)
P
P
P
Protein
Cascade
AKT
Protein
Cascade
P
Nucleus
EGF
ERBB2
ERBB2
P
P
Proliferation
Protein
Cascade
Survival
Nucleus
Apoptosis
How Can This Lead to Cancer?
ERBB2
P
Protein
Cascade
Proliferation
Nucleus
(Chen et al., 2006)
Tyrosine
Kinase
domain
ATP
TKI
ATP binding cleft on the kinase
(Chen et al., 2006)
(Pedersen et al., 2005)
(Pedersen et al., 2005)
(Chen et al., 2006)
P
P
P
Protein
Cascade
AKT
Protein
Cascade
P
Nucleus
What Are the Roles of Proteins
Associated with Lung Cancer?
http://www.taconichills.k12.ny.us/webquests/noncomdisease/lungcancerpic.jpg
Recap
Alanine
N-terminus
Tyrosine
C-terminus
P
P
P
Threonine
Leucine
Serine
Lysine
Nucleus
ERBB2
P
SH2
PI3K
P
Protein
Cascade
Change in
Gene
Expression
Nucleus
(Rikova et al. 2007)
(Jones et al. 2006)
Green and Blue circles
Red lines
Red circles
=
=
=
Proteins involved in cascade
Interactions
EGFR Receptor
(Jones et al. 2006)
No. protein receptors
No. protein receptors
No. protein receptors
Affinity Threshold (nM)
Affinity Threshold (nM)
Affinity Threshold (nM)
http://en.wikipedia.org/wiki/Proteins
(Rikova et al. 2007)
Amount of overphosphorylated protein in samples
50
45
40
35
Tumor
Samples
30
Cell Lines
25
20
15
10
5
0
ROS
ALK
MET
PDGFRα ErbB2
EGFR VEGFR-1
Chart configured from Table1 of Rikova et al. 2007
(Engelman et al., 2007)
P
P
P
Protein
Cascade
AKT
Protein
Cascade
P
Nucleus
http://www.taconichills.k12.ny.us/webquests/noncomdisease/lungcancerpic.jpg
http://www.researchvegf.com/researchvegf/multimedia/index.m#type-slides
PDGF-β
VEGF-A
PDGFR-β
VEGFR
Tumors
Angiogenesis
P
SH2
P85-α
P110-α
P
P
P
PIP2
PIP3
P
P
PI3K
P
P
PTEN
Endothelial Cell
AKT
P
AKT
P
mTOR
Growth,
Translation
BAD
Apoptosis
P
P
MDM2
p53
Nucleus
Proto-Oncogene
Oncogene
Cancer Cell
(Chen et al., 2009)
Giemsa-Stained Cells
(Chen et al., 2009)
VEGF-A
PI3K
SH2
P85-α
P110-α
P
P
P
P
PIP2
PIP3
P
P
FLJ10540
P
VEGFR
P
PTEN
Endothelial Cell
AKT
Binds to ATP binding site of many enzymes:
p-PDGFR-β Inhibitor
Reduced IFP, Hypoxia
Decreased VEGF Expression
http://www.medicinescomplete.com/mc/martindale/2007/images/MRT9229C001.gif
Normal
Tumor
http://www.nature.com/nm/journal/v7/n9/images/nm0901-987-F1.gif
http://www.medscape.com/pi/editorial/clinupdates/2000/583/art-tu02.fig04.jpg
(Vlahovic et al. 2007)
Vlahovic et al. 2007
Imatinib
http://onctalk.com/wp-content/uploads/2008/01/angiogenesis-summary.jpg
P
P
P
Protein
Cascade
AKT
Protein
Cascade
P
Nucleus
(Rosenberg et al., 1969)
Simple Diffusion
Nucleus
C-Abl
P53
NH3
NH3
Pt
G
G
P73
?
HMG1
Cell Cycle
Arrest
&
Apoptosis
Pt
Transporter
protein
Pt
Transporter
protein
Pt
Pt
Pt
Pt
nucleus
(Hall et al., 2007)
NH3
nucleus
Pt
G
G
NH3
1,2-intrastrand
d(GpG)adduct
crosslink
(Ohndorf et al., 1999)
Cell Cycle Arrest
&
Apoptosis
http://www.unc.edu/~shantanu/images/bkstcg_aacr07.png
HMGB
P73
Apoptosis
HMGB
P53
Pt-DNA Adduct
(Stross et al., 2002)
*Nucleotides
crosslinked
Bold- nucleotides
contacted by the
protein
(Ohndorf et al., 1999)
(Ohndorf et al., 1999)
?
Simple Diffusion
Nucleus
C-Abl
P53
NH3
NH3
Pt
G
G
P73
?
HMG1
Cell Cycle
Arrest
&
Apoptosis
cisplatin
homologue of
p53
Tumor
suppresor
tyrosine
kinase
mismatch
repair protein
(Gong et al., 1999)
MLH1-/P53
knockout=
& Abl= less
less sensitive
sensitive to
to CDDP,
CDDP survived
, survivedbetter
betterthan
thanwild
wildtype
typein
lower
in
lower
concentrations
concentrations
of of
CDDP
CDDP
(Gong et al., 1999)
Nucleus
NH3
Simple Diffusion
NH3
Pt
G
G
ATM
P53
P
Cell Cycle
Arrest
&
Apoptosis
C-Abl
Transporter
Proteins
P73
Protein
Cascade
P
Nucleus
P
P
P
Protein
Cascade
AKT
Protein
Cascade
P
Nucleus
http://www.specialityformulations.com/pcat-gifs/products-small/imatinib.jpg
http://immunodefence.com/ii/gefitinib.gif
http://www.themesotheliomalibrary.com/cisplatin.jpg



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

How does cisplatin enter the nucleus?

Roles and mechanisms behind the various
mutated proteins involved in lung cancer

New drugs , secondary mutations
Professor Sleiter
Schmooing yeast!!!
Dr. DebBurman
Mike Fiske
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