Cancer: Modeling Different Methods to Control It A SMART Team Project

1. Cancer: Modeling Different Methods to Control It A SMART Team Project By: Kaoley Vue, KaoSong Xiong, Mitchell Asplund, Ching Vang, Derek Unrau I’m coming along, too!

2. http://media-2.web.britannica.com/eb-media/15/67715-004-AD923748.gifhttp://media-2.web.britannica.com/eb-media/15/67715-004-AD923748.gif Why Is It Important? • 2008: 182,460 (female); 1,990 (male) have breast cancer • Deaths: 40,480 (female); 450 (male) • "The overall cost for treating a typical breast cancer will top $50,000 or even $100,000." -Dr. Stephen Edge • http://www.cancer.gov/cancertopics/types/breast

3. What’s The Focus? • Research and have an understanding of how cells develop into cancer cells • To build a model representing the protein • Have a better understanding on the treatments given to patients • Cure?

4. Students ModelingA Research Topic • Group of students • Explore science as a process, not facts • Model protein of study • Presentations

5. Why Join SMART Team? • Looking for Honors Work as LEAP students • Topic: Cancer (Mainly breast cancer) • Looked easy • Extremely difficult • Engaged our knowledge Do you have to be smart?

6. Students Part of SMART Team • Group 1: Kaoley Vue, KaoSong Xiong, Mitchell Asplund, Ching Vang, Derek Unrau • Group 2: Shaenah Maguire, Erin Lawrence, Jim Slogar, Samuel Joswiak • Group 3: Colton Cummings, Thomas Fish, Addela Marzofka, Brady Sebo

7. Leukemia cancer cells Cancer: What is it? • Organs made of cells • Cells divide & multiply when our body need them • Keeps dividing; too much • Result is a mass or growth; tumor • Can be benign or malignant

8. Breast Cancer Leukemia Lung Cancer Pancreatic Cancer Kidney Cancer Bladder Cancer Thyroid Cancer Prostate Cancer Common Types of Cancer Breast cancer cell Lung cancer cell dividing. Prostate cancer cell. www.hopeforcancer.com/images/BreastCancerCell.jpg http://www.sanger.ac.uk/Info/Press/gfx/070307_lung-cancer-cells_300.jpg http://www.chemlin.net/news/2006/sep2006/images/prostate-cancer-cell.jpg • http://www.cancer.gov/cancertopics/commoncancers

9. About 200 different types No single cause for any one type Multifactorial Carcinogen Age Genetic make up Immune systems Viruses Day to day environment (smoke, sun, manmade radiation, etc.) Bacterial infections It’s Causes • http://www.cancerhelp.org.uk/help/default.asp?page=119#multi_fact

10. http://www.nlm.nih.gov/MEDLINEPLUS/ency/images/ency/fullsize/18013.jpghttp://www.nlm.nih.gov/MEDLINEPLUS/ency/images/ency/fullsize/18013.jpg Controlling Cancer • Chemotherapy • Radiation Therapy • Hormonal Therapy • Targeted Therapy (Our Main Focus) • Biological Therapy • http://patient.cancerconsultants.com/CancerTreatment.aspx http://graphics8.nytimes.com/images/2007/08/01/health/adam/9805.jpg

11. How Does This Happen? • Firefighters, police, investigators… • “first messenger,” dispatcher “receptor,” firefighters “second messengers.” Communication is the key to success.

12. One Particular Focus… • Main Focus: Tyrosine receptor kinase (RTK) • Caused by uncontrolled and inaccurate communication between cells • High affinity cell surface receptor • Critical role in developing and progression of cancers

13. What is Tyrosine Receptor Kinase and ATP? Let Me Take These! • Multifunctional nucleotide • Plays an important role in cell biology as a coenzyme ATP

14. Tyrosine Kinase: What Is It? Ask Me • Enzyme: Transfers phosphate group from ATP (Adenosine triphospate) to tyrosine residue in a protein • Phosphorylation - the addition of a phosphate (PO4) group to a protein or other organic molecule. • Cascade of events; transmit the extracellular signal to nucleus • Gene changes • Result: A hyper-active receptor

15. EGF Background http://www.nndb.com/people/687/000132291/stanley-cohen.jpg • Dr. Stanley Cohen (Biochemist) • Produced by cell and transported to the membrane • Enabled scientists to further explore the cell growth process • Certain cells have this • Highly concentrated • Used in cells that are epidermal in nature

16. Why is EGF produced? • Regulate cell division • Needs to be a way to regulate Hey! It DOES look like a mouse! Rainbow colored NMR structure of the mouse epidermal growth factor http://en.wikipedia.org/wiki/Epidermal_growth_factor#cite_note-pmid10082370-0

17. EGFR • Cell-Surface Receptor • Member of the ErbB family • Attached to the cell's plasma membrane • Regulate cell division • Involved in breast cancer, lung cancer, and more http://discover8.com/public/images/upload_article_images/egf.jpg

18. Pathways • The RAS/ERK pathway • PI3 Kinase/AKT pathway • JAK/STAT pathway • RAS/ERK: Promotes cell division • PI3 Kinase/AKT: Cell survival • JAK/STAT: Regulation of cellular responses to cytokines and growth factors • http://www.abcam.com/index.html?pageconfig=resource&rid=10723&pid=10628

19. RAS/ERK Pathway • EGF activates EGFR • Binding Grb2 or Shc to phosphorylated ErbB • Recruits SOS (son of sevenless) • SOS activates RAS activates RAF-1 • So on and so forth until cell divides

20. I’m gonna go take a nap….

21. Activation of EGFR • Dimerization: Chemical or biological entity (consists of 2 monomers) • Held together by intramolecular forces or weaker intermolecular forces • Hangs out on membrane as monomer • Needs dimerization to enable the auto-trans-phosphorylation • Phosphorylates other monomer

22. But, before I go…what does this picture mean again?

23. Carcinogenesis: How It Happens • Stage 1: INITIATION *Mistakes when DNA is copied from one cell to another *Introduces a genetic error to the cell’s offspring * Can happen spontaneously or be inherited * Genes usually fix it; if can’t, suicide * If gene’s damaged, defense mechanism lost

24. Stage 2: PROMOTION • Mutation leads to mutation = Cancer • Starts promoting cell growth when restricted • Multiplies uncontrollably • Genes that control cell death become altered; no suicide • Damaged cell continue to reproduce; passing on mistakes • Advantage; acquire additional genetic changes http://www.empowher.com/media/reference/kidney-cancer

25. Stage 3: PROGRESSION zZzzZ…. • Tumors have a life of their own • Need blood and oxygen to survive • Develops own blood vessels that connect to body • Possible to spread through body • Breaks loose from original tumor and floats through bloodstream to other parts of the body where they attach themselves to healthy tissues • Invade normal tissues, new blood vessels, overgrow normal tissues

26. Stage 3: PROGRESSION • Tumors have a life of their own • Need blood and oxygen to survive • Develops own blood vessels that connect to body • Possible to spread through body • Breaks loose from original tumor and floats through bloodstream to other parts of the body where they attach themselves to healthy tissues • Invade normal tissues, new blood vessels, overgrow normal tissues http://www.themesotheliomalibrary.com/tnm-staging.jpg

27. Stage 3: Progression Continued • Have more mutations than the cells in original tumor • Spreading cancer harder to kill • More deadly than the original • New tumors acquire more changes to resist effective treatment • http://www2.mdanderson.org/depts/oncolog/articles/04/9-sep/9-04-hc.html

28. Movie To Explain • Part 1 and 2: A Clearer Understanding

29. Hmmmm…so ? ? How Do We Control/Get Rid of It? ? • Removal of tumor • Chemotherapies (drugs that can kill cancer cells) • Radiation therapies • Drugs

30. Control/Get Rid of Cancer • Hormone Therapy:An approach that controls/blocks hormones’ ability to promote tumor growth. • Biological Therapy:Takes advantage of body's own immune or hormonal system to act on cancer cells - while leaving healthy cells intact

31. Control/Get Rid of Cancer Continued • Targeted Therapy:Medication that blocks the growth of cancer cells • Interferes with specific targeted molecules needed for carcinogenesis and tumor growth

32. Our SMART Team’s Job • Illustrate modeling effectiveness in combating cancer • In the process show • How a drug inhibits EGFR • Another potential site to stop uncontrolled cell division

33. Background Knowledge First purified protein gets crystallized Calcium protein crystallized http://www.laurentian.ca/Laurentian/Home/Departments/Behavioural+Neuroscience/Pictures/Histology.htm?imgidx=3&Laurentian_Lang=en-CA

34. X-ray Crystallography • Bombard a crystallized sample with X-rays • Leaves an “image” • http://upload.wikimedia.org/wikipedia/en/thumb/e/e3/X-ray_crystallography.svg/691px-X-ray_crystallography.svg.png

35. Steps in Determining a Protein’s Structure Using X-Ray Crystallography http://en.wikipedia.org/wiki/Image:X_ray_diffraction.png#file

36. X Ray Crystallography data obtained from the Protein Data Bank Notice the X,Y, Z coordinates are given for each atom from the X-ray Data

37. Epidermal Growth Factor Receptor Space filled model of EGFR

38. Epidermal Growth Factor Receptor Backbone structure of EGFR

39. EGFR With And Without Drug Lapatinib

40. Lapatinib: Two differentmodels of the atom structure

41. EGFR

42. Drugs that Inhibit Clinical Development GW572016 (Lapatinib) http://www.roche.co.nz/images/logos/46.jpg OSI-774 (Tarceva) ZD-1839 (Iressa) https://www.tykerb.com/images/tykerb-logo.jpg http://www.pharmacyrxworld.com/productimages/iressa.jpg

43. The Drug The Drug The K-value (Tendency to grab ontoEGFR) The K-value (Tendency to grab onto EGFR) Our drug GW572016(Lapatinib) Our drugGW572016 (Lapatinib) 3.0 3.0 OSI-774 (Tarceva) OSI-774 (Tarceva) 0.4 0.4 ZD-1839 (Iressa) ZD-1839 (Iressa) 0.7 0.7

44. RAS/ERK Pathway • EGF activates EGFR • Binding Grb2 or Shc to phosphorylated ErbB • Recruits SOS (son of sevenless) • SOS activates RAS activates RAF-1 • So on and so forth until cell divides

45. RAS Another Site to Interfere with Cancer Progression

46. RAS: The Active Site

47. RAS: The Active Site Side View And Profile

48. RAS: The Active Site & The Groove Spot of great interest

49. Overall Cancer Views • Still much to learn for cancer drugs • Cure? • Treatment may not be success • Blocked pathway = a new route for cancer cells • Tumors: shrink, pores shrink (blood vessels around); larger molecules in drug are ineffective Of course there’s much to learn; you’re no expert or scientist!

50. Overall Cancer Views Continued • Better characterization of patients in trials • Tumors: biopsied & characterized on molecular and cellular level • Chance of relapse