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Controlling Cancer

Controlling Cancer. Shaenah Maguire, Sam Joswiak, Jim Slogar, Erin Lawrence. Estimated US Cancer Cases (2009). Men: 766,130. Women: 713,220. Prostate 25% Lung & bronchus 15% Colon & rectum 10% Urinary bladder 7% Melanoma of skin 5%

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Controlling Cancer

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  1. Controlling Cancer Shaenah Maguire, Sam Joswiak, Jim Slogar, Erin Lawrence

  2. Estimated US Cancer Cases (2009) Men: 766,130 Women: 713,220 Prostate 25% Lung & bronchus 15% Colon & rectum 10% Urinary bladder 7% Melanoma of skin 5% Non-Hodgkin lymphoma 5% Kidney & renal pelvis 5% Leukemia 3% Oral cavity 3% Pancreas 3% All Other Sites 19% 27% Breast 14% Lung & bronchus 10% Colon & rectum 6% Uterine corpus 4% Non-Hodgkin lymphoma 4% Melanoma of skin 4% Thyroid 3% Kidney & renal pelvis 3% Ovary 3% Pancreas 22% All Other Sites

  3. SMART Team • Students Modeling AResearch Topic

  4. Our Goal… • To understand cell processes, and the differences for cancer cells • Model and describe how cancer can be controlled

  5. Project • Part I • Write a 200-250 word abstract describing how tyrosine kinase domain of the epidermal growth factor receptor functions in normal cell division, and what role this protein plays in breast cancer. The abstract should also address the role that the inhibitor, lapatinib, plays in treating women with breast cancer • Part II • Design a model of the tyrosine kinase domain of the epidermal growth factor receptor using the parameter set forth in the Qualification Challenge

  6. Project Continued.. • Part III • Write a 200-250 word abstract describing the function of the Ras and its role in the cell signaling pathway to induce cell division • Part IV • Design a model of the GTP Binding Domain

  7. Normal Cell Processes

  8. EGFR • A signal is received by one of many EGFR (Epidermal Growth Factor Receptors) of a cell • It binds with another EGFR, activating the tyrosine kinase enzymes EGFR Tyrosine kinase

  9. Tyrosine Kinase • Used to transmit signals and control cell processes • Includes growth, differentiation, metabolism, adhesion, motility, death

  10. GRB2-SOS Activation • The 6 tyrosine kinases of EGFR become phosphlorated • Proteins such as GRB2-SOS bind to it, becoming active • http://www.expertreviews.org/02004441h.htm

  11. RAS • RAS releases GDP which is exchanged for GTP • GTP binds to RAS, activating it http://jkweb.mcb.berkeley.edu/external/research-in-progress/5-3/signaling/ras_sos_schematic1.jpg

  12. Into the Nucleus.. • This activates raf-1, then MEK and MPKA, which goes into the nucleus & tells it to divide

  13. Abnormal Cell Growth

  14. Cancer abilities • Uncontrolled replication- doesn’t need signals • No signal to die (apoptosis) • Can metastasize- move to other parts of the body

  15. Ways to Control Cancer…

  16. Options • Mastectomy (breast cancer) • Removal of Tumor • Chemotherapy • Radiation Therapy • Drugs

  17. Hormone Therapy • Block or lower the effect of estrogen receptors on breast cancer cells • Tamoxifen and toremifene (Fareston):Temporarily blocks estrogen receptors, helps reduce risk of developing breast cancer

  18. Biological Therapy • Uses Immune system • Make cancer cells more recognizable • Enhance the body's ability to repair or replace normal cells • Prevent cancer cells from spreading

  19. Targeted Therapy • Use drugs that block the growth and spread of cancer. • Lapatinib: Control Breast Cancer; EGFR inhibitor http://www.nature.com/nrclinonc/journal/v3/n5/images/ncponc0509-f1.jpg

  20. How are drugs selected?How can it be predicted which drugs might work?

  21. http://upload.wikimedia.org/wikipedia/en/thumb/e/e3/X-ray_crystallography.svg/691px-X-ray_crystallography.svg.pnghttp://upload.wikimedia.org/wikipedia/en/thumb/e/e3/X-ray_crystallography.svg/691px-X-ray_crystallography.svg.png Xray Crystallography • Bombard a sample with Xrays • leaves an “image where the density is greater. • This is where the atoms must be located. • Different atoms have different densities.

  22. Steps in Determining a Protein’s Structure Using X-Ray Crystallography • Relate to EGFR and the drugs.. http://en.wikipedia.org/wiki/Image:X_ray_diffraction.png#file

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

  24. Rasmol • Program used • to make the models • Manipulate the molecules • Uses xray crystallography information from a world-wide data bank showing various protein structures. • We used 1XKK (EGFR) and 5P21 (RAS)

  25. EGFR

  26. FMM Lapatinib

  27. Drug’s Impact EGFR Lapatinib

  28. Blocks signaling in EGFR Falls out at a certain point, so the cell doesn’t just die Lapatinib

  29. Other Drugs… bigger number, the better

  30. RAS (activated) *Looking for a drug to fit in here, help with abnormal signaling *Cover it to prevent GTP from going there

  31. Modeling…Importance • Here are two different ways that cancer is attempted to be blocked… • X-ray crystallography and its associated modeling have allowed people to make predictions as to what chemicals/drugs might work for treatment, how diseases such as cancer can be treated.

  32. Conclusion • Modeling helps visualize • Shared some possible treatments • Hopefully we have given you a better image as to how cancer is combated, how modeling helps…

  33. A Special Thanks to… • Dr. Shannon Colton, • Dr. Margaret Franzen, • Dr. Tim Herman Center for Biological Modeling, Milwaukee School of Engineering, Thanks to Brandon Radloff and Jon Hohol for their initial help in Rasmol training Mr. Heeren

  34. Bibliography “1XKK.” RCSB Protein Data Bank. RCSB. 22 Apr. 2009 <http://www.rcsb.org/pdb/explore.do?structureId=1XKK>. • “5P21.” RCSB Protein Data Bank. RCSB. 22 Apr. 2009 <http://www.rcsb.org/pdb/explore/explore.do?structureId=5P21>. • “Biotherapy / Immunotherapy.” Cancer Treatment Centers of America. Cancer Treatment Centers of America. 29 Apr. 2009 <http://www.cancercenter.com/conventional-cancer-treatment/biotherapy- immunotherapy.cfm?source=googlemw&c=Google_Midwest_Core:General_ Biological_Therapy:biological_therapy:Exact&ef_id=1812:3:s_94578445c51f f44f08be23993ba17125_2607217011:gCHM1UGvMaAAABgVdPcAAAAN:2 0090429121300>. • “Chemical Communication in Cells.” Biology of Cancer. University of Colorado. 22 Apr. 2009 <http://mama.uchsc.edu/vc/cancer/signal/p1.cfm>. • Cloford. “500+ Colors.” Cloford.com. 2000. Cloford. 22 Apr. 2009 <http://cloford.com/resources/colours/500col.htm>.

  35. Bibliography Continued • Goodsell, David S. “The Molecular Perspective: Epidermal Growth Factor.” The Oncologist. 2003. AlphaMed Press. 22 Apr. 2009 <http://theoncologist.alphamedpress.org/cgi/content/full/8/5/496#F1>. • “Hormonal Therapy.” BreastCancer.Org. 27 Feb. 2009. BreastCancer.Org. 29 Apr. 2009 <http://www.breastcancer.org/treatment/hormonal/>. • “MAP Kinase Pathways.” Biocreations. 2006. Biocreations. 22 Apr. 2009 <http://www.biocreations.com/animations/MAP_Kinase.swf>. • RasMol. RasMol. 21 Mar. 2008. 22 Apr. 2009 <http://www.openrasmol.org/>. • “Receptor Tyrosine Kinase Animation.” Wiley. Wiley. 22 Apr. 2009 <http://www.wiley.com/college/fob/quiz/quiz21/21-15.html>. • “Targeted Cancer Therapies: Questions and Answers.” National Cancer Institute. National Cancer Institute. 29 Apr. 2009 <http://www.cancer.gov/cancertopics/factsheet/Therapy/targeted>.

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