Lung Cancer: The Breathtaking Battle of TKIs and EGFR Mutants - PowerPoint PPT Presentation

bobby hodges elizabeth ross natalie simak keith solvang and eliot vildaver n.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
Lung Cancer: The Breathtaking Battle of TKIs and EGFR Mutants PowerPoint Presentation
Download Presentation
Lung Cancer: The Breathtaking Battle of TKIs and EGFR Mutants

play fullscreen
1 / 90
Lung Cancer: The Breathtaking Battle of TKIs and EGFR Mutants
126 Views
Download Presentation
zelenia-warren
Download Presentation

Lung Cancer: The Breathtaking Battle of TKIs and EGFR Mutants

- - - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript

  1. Bobby Hodges, Elizabeth Ross, Natalie Simak, Keith Solvang and Eliot Vildaver Lung Cancer: The Breathtaking Battle of TKIs and EGFR Mutants

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

  3. 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

  4. http://img.quamut.com/chart/9471/02_healthy_sick_x-ray.jpg

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

  6. Where Are We Headed? http://www.freefoto.com/images/21/16/21_16_2---Single-Carriageway-Road_web.jpg

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

  8. History of Lung Cancer http://www.icowman.com/uploadfiles/2007072409225175.jpg http://www.icowman.com/uploadfiles/2007072409225175.jpg

  9. 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

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

  11. 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

  12. Epidemiology http://medicineworld.org/cancer/lung/ http://images.google.com/

  13. 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

  14. EGF ERBB2 Cisplatin Imatinib Protein Cascade Gefitinib EGFR P ? Nucleus ?

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

  16. Implications of Chromosomal Loci in the Development of Lung Cancer http://academic.evergreen.edu http://rosenblumtv.files.wordpress.com http://www.pharmgkb.org

  17. Chromosomes • Compact structures of DNA • Contains thousands of genes Chromatid Centromere Genes http://staff.jccc.net/PDECELL/celldivision/chromosome1.gif

  18. 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

  19. 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

  20. Identifying Regions On Chromosomes 6 Regions Away p-arm Centromere Region 5q6 q-arm 5 http://images.google.com/

  21. Three Regions of Association http://upload.wikimedia.org/ http://upload.wikimedia.org/

  22. 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

  23. How were these regions discovered? (Hung et al., 2008)

  24. 15q24 highly linked with smoking behavior (Thorgeirson et al., 2008)

  25. TERT gene found on 5p15.33 Cancerous Growth http://images.google.com/i

  26. 5p15.33 shows similar results (McKay et al., 2008)

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

  28. How Do Cells Proliferate?

  29. EGFR/ERBB2 Forms a Heterodimer EGFR EGFR EGF EGFR ERBB2 ERBB2 P P Proliferation Protein Cascade Survival Nucleus Apoptosis

  30. How Can This Lead to Cancer?

  31. Mutated EGFR Leads to Cancer ERBB2 EGFR P Protein Cascade Proliferation Nucleus

  32. Mutated EGFRs have Distinct Patterns of Tyr Phosphorylation (Chen et al., 2006)

  33. Tyrosine Kinase Inhibitors (TKIs)Gefitinib EGFR Tyrosine Kinase domain ATP TKI ATP binding cleft on the kinase

  34. Gefitinib Suppresses Phosphorylation of Most EGFR Mutants (Chen et al., 2006)

  35. What About the Proteins in the Signaling Pathway?

  36. Effectiveness of Gefitinib is Dependent on Concentration (Pedersen et al., 2005)

  37. High Doses of Gefitinib Decreases Proliferation of Mutated EGFR Cells (Pedersen et al., 2005)

  38. Gefitinib has Variable Growth-Inhibitory Effects (Chen et al., 2006)

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

  40. What Are the Roles of Proteins Associated with Lung Cancer? http://www.taconichills.k12.ny.us/webquests/noncomdisease/lungcancerpic.jpg

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

  42. How Does The Pathway Work?

  43. Domain Attraction ERBB2 P P PI3K Protein Cascade SH2 Change in Gene Expression Nucleus

  44. Why are EGFR and ERBB2 Special?

  45. Main Contributors to NSCLC (Rikova et al. 2007)

  46. Link between Concentration and Interaction (Jones et al. 2006) Green andBlue circles = Proteins involved in cascade Interactions Red lines = Red circles = EGFR Receptor

  47. 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)

  48. Are there other types of Proteins? http://en.wikipedia.org/wiki/Proteins

  49. Other Contributors to NSCLC (Rikova et al. 2007)

  50. Specifically, some proteins more than others Amount of overphosphorylated protein in samples Chart configured from Table1 of Rikova et al. 2007