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Bobby Hodges, Elizabeth Ross, Natalie Simak , Keith Solvang and Eliot Vildaver. Lung Cancer: The Breathtaking Battle of TKIs and EGFR Mutants. Diseased Genome Hospital. http:// blogs.usask.ca/medical_education/archive/ElksRehabFront%2520Door.jpg.

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slide2

Diseased

Genome

Hospital

http://blogs.usask.ca/medical_education/archive/ElksRehabFront%2520Door.jpg

slide3

http://1.bp.blogspot.com/_HI2mCx5P3H0/SLlEQoHj8AI/AAAAAAAAA8Q/My7tf78TNc8/s320/hospital-bed-786282.jpghttp://1.bp.blogspot.com/_HI2mCx5P3H0/SLlEQoHj8AI/AAAAAAAAA8Q/My7tf78TNc8/s320/hospital-bed-786282.jpg

slide5

http://www.cardiothoracicsurgery.org/content/2/1/16/figure/F1?highres=yhttp://www.cardiothoracicsurgery.org/content/2/1/16/figure/F1?highres=y

where are we headed
Where Are We Headed?

http://www.freefoto.com/images/21/16/21_16_2---Single-Carriageway-Road_web.jpg

cancer
Cancer

http://www.odec.ca/projects/2005/thog5n0/public_html/Tumour.gif

history of lung cancer
History of Lung Cancer

http://www.icowman.com/uploadfiles/2007072409225175.jpg

http://www.icowman.com/uploadfiles/2007072409225175.jpg

pathology
Pathology

Non Small Cell

Small Cell

Bronchi

Grows rapidly

Spreads quickly

  • Squamous cell carcinoma
  • Adenocarcinoma
  • Large-cell carcinoma

http://images.google.com/imgres?imgurl=http://upload.wikimedia.org/

Lynch et al., (2004)

http://images.google.com/imgres?imgurl=http://www.dkimages.com/discover/previews/852/20223038.JPG

risk factors
Risk Factors

http://www.taconichills.k12.ny.us/webquests/noncomdisease/lungcancerpic.jpg

you are not alone
You Are Not Alone
  • 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

epidemiology
Epidemiology

http://medicineworld.org/cancer/lung/

http://images.google.com/

what next
What Next?

While there is no known cure as of right now, there ARE options!

Imatinib

Gefinitib

Cisplatin

http://dspace.mit.edu

http://dspace.mit.edu

slide14

EGF

ERBB2

Cisplatin

Imatinib

Protein

Cascade

Gefitinib

EGFR

P

?

Nucleus

?

slide15

P

VEGF-A

EGF

MET

P

ERBB2

P

PI3K

Imatinib

Cisplatin

Gefitinib

Protein

Cascade

Protein

Cascade

EGFR

P

AKT

PDGFR

P

Nucleus

implications of chromosomal loci in the development of lung cancer
Implications of Chromosomal Loci in the Development of Lung Cancer

http://academic.evergreen.edu

http://rosenblumtv.files.wordpress.com

http://www.pharmgkb.org

chromosomes
Chromosomes
  • Compact structures of DNA
  • Contains thousands of genes

Chromatid

Centromere

Genes

http://staff.jccc.net/PDECELL/celldivision/chromosome1.gif

single nucleotide polymorphisms snps
Single Nucleotide Polymorphisms (SNPs)
  • 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

genome wide association studies
Genome-wide Association Studies
  • 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

identify ing regions on chromosomes
Identifying Regions On Chromosomes

6 Regions Away

p-arm

Centromere

Region 5q6

q-arm

5

http://images.google.com/

three regions of association
Three Regions of Association

http://upload.wikimedia.org/

http://upload.wikimedia.org/

nicotinic acetylcholine receptor genes found on 15q24 and 15q25
Nicotinic Acetylcholine Receptor Genes Found on 15q24 and 15q25

http://www.jyi.org/articleimages/88/originals/img0.jpg

Nicotine binds and stimulates acetylcholine ion channel-linked in neurons

tert gene found on 5p15 33
TERT gene found on 5p15.33

Cancerous Growth

http://images.google.com/i

5p15 33 shows similar results
5p15.33 shows similar results

(McKay et al., 2008)

slide27

P

VEGF-A

EGF

MET

P

ERBB2

P

PI3K

Imatinib

Cisplatin

Gefitinib

Protein

Cascade

Protein

Cascade

EGFR

P

AKT

PDGFR

P

Nucleus

egfr erbb2 forms a heterodimer
EGFR/ERBB2 Forms a Heterodimer

EGFR

EGFR

EGF

EGFR

ERBB2

ERBB2

P

P

Proliferation

Protein

Cascade

Survival

Nucleus

Apoptosis

mutated egfr leads to cancer
Mutated EGFR Leads to Cancer

ERBB2

EGFR

P

Protein

Cascade

Proliferation

Nucleus

tyrosine kinase inhibitors tkis gefitinib
Tyrosine Kinase Inhibitors (TKIs)Gefitinib

EGFR

Tyrosine

Kinase

domain

ATP

TKI

ATP binding cleft on the kinase

slide39

P

VEGF-A

EGF

MET

P

ERBB2

P

PI3K

Imatinib

Cisplatin

Gefitinib

Protein

Cascade

Protein

Cascade

EGFR

P

AKT

PDGFR

P

Nucleus

slide40

What Are the Roles of Proteins Associated with Lung Cancer?

http://www.taconichills.k12.ny.us/webquests/noncomdisease/lungcancerpic.jpg

slide41

Recap

Alanine

N-terminus

Tyrosine

P

P

C-terminus

P

Nucleus

Threonine

Leucine

Serine

Lysine

domain attraction
Domain Attraction

ERBB2

P

P

PI3K

Protein Cascade

SH2

Change in Gene Expression

Nucleus

main contributors to nsclc
Main Contributors to NSCLC

(Rikova et al. 2007)

link between concentration and interaction
Link between Concentration and Interaction

(Jones et al. 2006)

Green andBlue circles =

Proteins involved in cascade

Interactions

Red lines =

Red circles =

EGFR Receptor

other erbb2 associations
Other ERBB2 Associations

No. protein receptors

No. protein receptors

No. protein receptors

Affinity Threshold (nM) Affinity Threshold (nM) Affinity Threshold (nM)

(Jones et al. 2006)

are there other types of proteins
Are there other types of Proteins?

http://en.wikipedia.org/wiki/Proteins

other contributors to nsclc
Other Contributors to NSCLC

(Rikova et al. 2007)

specifically some proteins more than others
Specifically, some proteins more than others

Amount of overphosphorylated protein in samples

Chart configured from Table1 of Rikova et al. 2007

slide52

P

VEGF-A

EGF

MET

P

ERBB2

P

PI3K

Imatinib

Cisplatin

Gefitinib

Protein

Cascade

Protein

Cascade

EGFR

P

AKT

PDGFR

P

Nucleus

what is the role of angiogenesis in lung cancer
What is the Role of Angiogenesis in Lung Cancer?

http://www.taconichills.k12.ny.us/webquests/noncomdisease/lungcancerpic.jpg

angiogenesis and vegf
Angiogenesis and VEGF

http://www.researchvegf.com/researchvegf/multimedia/index.m#type-slides

tumor angiogenesis is unregulated
Tumor Angiogenesis Is Unregulated

PDGF-β

VEGF-A

PDGFR-β

VEGFR

Tumors

Angiogenesis

pi3k akt pathway in lung cancer
PI3K / Akt Pathway in Lung Cancer

P

P

P

PIP3

P85-α

P110-α

PIP2

SH2

P

P

P

PI3K

AKT

P

P

PTEN

Endothelial Cell

akt is a downstream regulator
Akt is a Downstream Regulator

Growth,

Translation

P

mTOR

P

Apoptosis

AKT

BAD

P

P

MDM2

p53

Nucleus

flj10540 is an oncogene
FLJ10540 Is An Oncogene

Oncogene

Proto-Oncogene

Cancer Cell

flj10540 mediates cell migration and invasion through pi3k akt
FLJ10540 Mediates Cell Migration and Invasion Through PI3K/Akt

Giemsa-Stained Cells

  • (Chen et al., 2009)
recap flj10540 missing link in pi3k akt
Recap: FLJ10540 Missing Link in PI3K/Akt

VEGF-A

P

PI3K

P

P

PIP3

P85-α

P110-α

PIP2

SH2

P

P

P

FLJ10540

AKT

P

VEGFR

P

PTEN

Endothelial Cell

imatinib is a tki
Imatinib is a TKI

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

imatinib targets ifp and hypoxia
Imatinib Targets IFP and Hypoxia

Normal

Tumor

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

imatinib treatment
Imatinib Treatment

Imatinib

http://onctalk.com/wp-content/uploads/2008/01/angiogenesis-summary.jpg

slide67

P

VEGF-A

EGF

MET

P

ERBB2

P

PI3K

Imatinib

Cisplatin

Gefitinib

Protein

Cascade

Protein

Cascade

EGFR

P

AKT

PDGFR

P

Nucleus

treatments
Treatments
  • Dr. Ross
    • Gefinitib
  • Dr. Vildaver
    • Imatinib
discovery of cisplatin
Discovery of Cisplatin

(Rosenberg et al., 1969)

old model of cisplatin
Old Model of Cisplatin

Nucleus

Cisplatin

Simple Diffusion

P73

P53

NH3

NH3

Pt

C-Abl

HMG1

?

G

G

?

HMG1

Cell Cycle Arrest

&

Apoptosis

how pt drugs enter cells
How Pt Drugs Enter Cells

Pt

Transporter

protein

Transporter

protein

Pt

Pt

Pt

Pt

Pt

nucleus

(Hall et al., 2007)

crosslinks
Crosslinks

NH3

nucleus

Pt

NH3

G

G

1,2-intrastrand d(GpG)adduct

crosslink

Cell Cycle Arrest

&

Apoptosis

(Ohndorf et al., 1999)

pt dna adduct
Pt-DNA adduct

http://www.unc.edu/~shantanu/images/bkstcg_aacr07.png

high mobility group proteins
High Mobility Group Proteins

HMGB

Apoptosis

Pt-DNA Adduct

P73

P53

HMGB

(Stross et al., 2002)

slide75

*Nucleotides crosslinked

  • Bold- nucleotides contacted by the protein

(Ohndorf et al., 1999)

phenylalanine mutations
Phenylalanine Mutations

(Ohndorf et al., 1999)

old model of cisplatin1
Old Model of Cisplatin

?

Nucleus

Cisplatin

Simple Diffusion

P73

P53

NH3

NH3

Pt

C-Abl

HMG1

?

G

G

?

HMG1

Cell Cycle Arrest

&

Apoptosis

2 distinct regulating mechanisms
2 Distinct Regulating Mechanisms

tyrosine kinase

cisplatin

mismatch repair protein

homologue of p53

Tumor suppresor

(Gong et al., 1999)

role of p73 in cell death
Role of p73 in Cell Death

MLH1-/- & Abl= less sensitive to CDDP , survived better than wild type in lower concentrations of CDDP

P53 knockout= less sensitive to CDDP, survived better than wild type in lower concentrations of CDDP

(Gong et al., 1999)

new model of cisplatin
New Model of Cisplatin

Nucleus

Cisplatin

Simple Diffusion

P53

P73

NH3

NH3

P

Transporter

Proteins

Pt

C-Abl

Cell Cycle Arrest

&

Apoptosis

HMG1

G

G

ATM

HMG1

slide81

EGF

ERBB2

Cisplatin

Imatinib

Protein

Cascade

Gefitinib

EGFR

P

?

Nucleus

?

slide82

P

VEGF-A

EGF

MET

P

ERBB2

P

PI3K

Imatinib

Cisplatin

Gefitinib

Protein

Cascade

Protein

Cascade

EGFR

P

AKT

PDGFR

P

Nucleus

cocktail of drugs

?

Cocktail of Drugs

http://www.specialityformulations.com/pcat-gifs/products-small/imatinib.jpg

http://immunodefence.com/ii/gefitinib.gif

http://www.themesotheliomalibrary.com/cisplatin.jpg

current future hypotheses
Current & Future Hypotheses
  • 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
future studies
Future Studies
  • How does cisplatin enter the nucleus?
  • Roles and mechanisms behind the various mutated proteins involved in lung cancer
  • New drugs , secondary mutations
acknowledgements
Acknowledgements

Professor Sleiter

Schmooing yeast!!!

?

acknowledgements1
Acknowledgements

Dr. DebBurman

references
References

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Agami, R., Blandino, G., Oren, M., and Shaul, Y. (1999). Interaction of c-Abl and p73alpha and their collaboration to induce apoptosis. Nature 399, 809-813.

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Alberts, B., Bray, D., Hopkin, K., Johnson, A., Lewis, J., Raff, M., Roberts, K., and Walter, P. 2004. Essential Cell Biology. Garland Science. New York, pp740.

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Jemal A, Siegel R, Ward E, Hao Y, Xu J, et al. (2008) Cancer statistics, 2008. CA Cancer J Clin 58: 71-96.

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