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Shaenah Maguire, Sam Joswiak, Jim Slogar, Erin Lawrence
Controlling Cancer Shaenah Maguire, Sam Joswiak, Jim Slogar, Erin Lawrence
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Estimated US Cancer Cases (2009)
Men: 766,130 Women: 713,220 Prostate % Lung & bronchus 15% Colon & rectum 10% Urinary bladder 7% Melanoma of skin 5% Non-Hodgkin lymphoma 5% Kidney & renal pelvis % Leukemia % Oral cavity % Pancreas % 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
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SMART Team Students Modeling A Research Topic
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Our Goal… To understand cell processes, and the differences for cancer cells Model and describe how cancer can be controlled
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Project Part I Write a 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
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Project Continued.. Part III Part IV
Write a 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
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Normal Cell Processes
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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
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Tyrosine Kinase Used to transmit signals and control cell processes
Includes growth, differentiation, metabolism, adhesion, motility, death
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GRB2-SOS Activation The 6 tyrosine kinases of EGFR become phosphlorated Proteins such as GRB2-SOS bind to it, becoming active
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RAS RAS releases GDP which is exchanged for GTP
GTP binds to RAS, activating it
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This activates raf-1, then MEK and MPKA, which goes into the nucleus & tells it to divide
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Abnormal Cell Growth
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Cancer abilities Uncontrolled replication- doesn’t need signals
No signal to die (apoptosis) Can metastasize- move to other parts of the body
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Ways to Control Cancer…
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Options Mastectomy (breast cancer) Removal of Tumor Chemotherapy
Radiation Therapy Drugs
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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
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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
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Targeted Therapy Use drugs that block the growth and spread of cancer.
Lapatinib: Control Breast Cancer; EGFR inhibitor
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How are drugs selected? How can it be predicted which drugs might work?
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Xray Crystallography Bombard a sample with Xrays
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.
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Steps in Determining a Protein’s Structure Using X-Ray Crystallography
Relate to EGFR and the drugs..
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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
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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)
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EGFR
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FMM Lapatinib
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Drug’s Impact EGFR Lapatinib
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Lapatinib Blocks signaling in EGFR
Falls out at a certain point, so the cell doesn’t just die
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bigger number, the better
Other Drugs… ErbB enzyme Inhibition by Compounds in Clinical Development Ki values a=Kiapp, b=IC50, c=cKiapp(nM) Compound EGFR ErbB-2 ErbB-4 GW 3 13 347 ZD 0.4 870 1130 OSI 0.7 1000 1530 CI 30 127 388 bigger number, the better
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RAS (activated) *Looking for a drug to fit in here, help with abnormal signaling *Cover it to prevent GTP from going there
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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.
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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…
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Center for Biological Modeling, Milwaukee School of Engineering,
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
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“1XKK.” RCSB Protein Data Bank. RCSB. 22 Apr. 2009
Bibliography “1XKK.” RCSB Protein Data Bank. RCSB. 22 Apr. 2009 < “5P21.” RCSB Protein Data Bank. RCSB. 22 Apr < “Biotherapy / Immunotherapy.” Cancer Treatment Centers of America. Cancer Treatment Centers of America. 29 Apr < immunotherapy.cfm?source=googlemw&c=Google_Midwest_Core:General_ Biological_Therapy:biological_therapy:Exact&ef_id=1812:3:s_ c51f f44f08be23993ba17125_ :gCHM1UGvMaAAABgVdPcAAAAN: >. “Chemical Communication in Cells.” Biology of Cancer. University of Colorado Apr < Cloford. “500+ Colors.” Cloford.com Cloford. 22 Apr <
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Bibliography Continued
Goodsell, David S. “The Molecular Perspective: Epidermal Growth Factor.” The Oncologist AlphaMed Press. 22 Apr < “Hormonal Therapy.” BreastCancer.Org. 27 Feb BreastCancer.Org. 29 Apr < “MAP Kinase Pathways.” Biocreations Biocreations. 22 Apr < RasMol. RasMol. 21 Mar Apr < “Receptor Tyrosine Kinase Animation.” Wiley. Wiley. 22 Apr < “Targeted Cancer Therapies: Questions and Answers.” National Cancer Institute. National Cancer Institute. 29 Apr <
