Controlling Cancer

Shaenah Maguire, Sam Joswiak, Jim Slogar, Erin Lawrence

Estimated US Cancer Cases (2009)

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%

Men: 766,130 Women: 713,220

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

SMART Team

Students Modeling A Research Topic

Our Goal…

To understand cell processes, and the differences for cancer cells

Model and describe how cancer can be controlled

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

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

Normal Cell Processes

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

Tyrosine Kinase

Used to transmit signals and control cell processes

Includes growth, differentiation, metabolism, adhesion, motility, death

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

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

Into the Nucleus..

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

Growth factors and map kinase Growth factors and map kinase

Fig. 14 Fig. 14 - - 18 18

Steps missing

Jun is part of

AP - 1.

Abnormal Cell Growth

Cancer abilities

Uncontrolled replication- doesn’t need signals

No signal to die (apoptosis)

Can metastasize- move to other parts of the body

Ways to Control Cancer…

Options

Mastectomy (breast cancer)

Removal of Tumor Chemotherapy Radiation Therapy Drugs

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

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

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

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

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.

•http://upload.wikimedia.org/wikipedia/en/thumb/e/e3/X-ray_crystallography.svg/691px-X-ray_crystallography.svg.png

http://en.wikipedia.org/wiki/Image:X_ray_diffraction.png#file

Steps in Determining a

Protein’s Structure Using X-Ray

Crystallography

•Relate to EGFR and the drugs..

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

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)

EGFR

FMM

Drug’s Impact

Lapatinib

Blocks signaling in EGFR

Falls out at a certain point, so the cell doesn’t just die

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

RAS (activated)

*Looking for a drug to fit in here, help with abnormal signaling

*Cover it to prevent GTP from going there

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.

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…

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 trainingMr. Heeren

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_94578445c51ff44f08be23993ba17125_2607217011:gCHM1UGvMaAAABgVdPcAAAAN:20090429121300>.

“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>.

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>.