Transcript Controlling Cancer Shaenah Maguire, Sam Joswiak, Jim Slogar, Erin

Controlling Cancer
Shaenah Maguire,
Sam Joswiak, Jim
Slogar, Erin
Lawrence
Estimated US Cancer Cases (2009)
Men: 766,130
Women: 713,220
Prostate
25%
27%
Breast
Lung & bronchus
15%
14%
Lung & bronchus
Colon & rectum
10%
10%
Colon & rectum
Urinary bladder
7%
6%
Uterine corpus
Melanoma of skin
5%
4%
Non-Hodgkin lymphoma
Non-Hodgkin lymphoma 5%
4%
Melanoma of skin
Kidney & renal pelvis
5%
4%
Leukemia
3%
3%
Kidney & renal pelvis
Oral cavity
3%
3%
Ovary
Pancreas
3%
3%
Pancreas
19%
22%
All Other Sites
All Other Sites
Thyroid
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
Fig. 14-18
Steps missing
Jun is part of
AP-1.
Abnormal Cell Growth
Cancer abilities



Uncontrolled replicationdoesn’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?
•http://upload.wikimedia.org/wikipedia
/en/thumb/e/e3/Xray_crystallography.svg/691px-Xray_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.
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
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 training
Mr. 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/biotherapyimmunotherapy.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>.
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>.