Controlling Cancer

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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 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 Pancr
eas 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 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

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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

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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
• http//www.expertreviews.org/02004441h.htm

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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
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Into the Nucleus..

• 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- doesnt 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

http//www.nature.com/nrclinonc/journal/v3/n5/imag
es/ncponc0509-f1.jpg
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How are drugs selected? How can it be
predicted which drugs might work?
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Xray Crystallography

• http//upload.wikimedia.org/wikipedia/en/thumb/e/e
  3/X-ray_crystallography.svg/691px-X-ray_crystallog
  raphy.svg.png

• 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 Proteins Structure Using
X-Ray Crystallography

• Relate to EGFR and the drugs..

http//en.wikipedia.org/wiki/ImageX_ray_diffracti
on.pngfile
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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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Drugs Impact
EGFR
Lapatinib
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Lapatinib

• Blocks signaling in EGFR
• Falls out at a certain point, so the cell doesnt
  just die

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Other Drugs
ErbB enzyme Inhibition by Compounds in Clinical Development Ki values ErbB enzyme Inhibition by Compounds in Clinical Development Ki values ErbB enzyme Inhibition by Compounds in Clinical Development Ki values ErbB enzyme Inhibition by Compounds in Clinical Development Ki values
aKiapp, bIC50, ccKiapp(nM) aKiapp, bIC50, ccKiapp(nM) aKiapp, bIC50, ccKiapp(nM) aKiapp, bIC50, ccKiapp(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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ModelingImportance

• 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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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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Bibliography

• 1XKK. RCSB Protein Data Bank. RCSB. 22 Apr.
  2009
• lthttp//www.rcsb.org/pdb/explore.do?structureId1
  XKKgt.
• 5P21. RCSB Protein Data Bank. RCSB. 22 Apr.
  2009 lthttp//www.rcsb.org/pdb/explore/explore.do?
  structureId5P21gt.
• Biotherapy / Immunotherapy. Cancer Treatment
  Centers of America. Cancer Treatment Centers of
  America. 29 Apr. 2009 lthttp//www.cancercenter.c
  om/conventional-cancer-treatment/biotherapy- immun
  otherapy.cfm?sourcegooglemwcGoogle_Midwest_Core
  General_ Biological_Therapybiological_therapyEx
  actef_id18123s_94578445c51f f44f08be23993ba171
  25_2607217011gCHM1UGvMaAAABgVdPcAAAAN2 009042912
  1300gt.
• Chemical Communication in Cells. Biology of
  Cancer. University of Colorado. 22 Apr. 2009
  lthttp//mama.uchsc.edu/vc/cancer/signal/p1.cfmgt.
• Cloford. 500 Colors. Cloford.com. 2000.
  Cloford. 22 Apr. 2009 lthttp//cloford.com/resour
  ces/colours/500col.htmgt.

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Bibliography Continued

• Goodsell, David S. The Molecular Perspective
  Epidermal Growth Factor. The Oncologist. 2003.
  AlphaMed Press. 22 Apr. 2009 lthttp//theoncologi
  st.alphamedpress.org/cgi/content/full/8/5/496F1gt.
  
• Hormonal Therapy. BreastCancer.Org. 27 Feb.
  2009. BreastCancer.Org. 29 Apr. 2009
  lthttp//www.breastcancer.org/treatment/hormonal/gt.
  
• MAP Kinase Pathways. Biocreations. 2006.
  Biocreations. 22 Apr. 2009 lthttp//www.biocreati
  ons.com/animations/MAP_Kinase.swfgt.
• RasMol. RasMol. 21 Mar. 2008. 22 Apr. 2009
  lthttp//www.openrasmol.org/gt.
• Receptor Tyrosine Kinase Animation. Wiley.
  Wiley. 22 Apr. 2009 lthttp//www.wiley.com/colleg
  e/fob/quiz/quiz21/21-15.htmlgt.
• Targeted Cancer Therapies Questions and
  Answers. National Cancer Institute. National
  Cancer Institute. 29 Apr. 2009
  lthttp//www.cancer.gov/cancertopics/factsheet/The
  rapy/targetedgt.