Download Tyrosine Kinase

Cancer: Modeling Different
Methods to Control It
A SMART Team Project
By: Kaoley Vue, KaoSong Xiong,
Mitchell Asplund, Ching Vang,
Derek Unrau
I’m coming
along, too!
http://media-2.web.britannica.com/eb-media/15/67715-004-AD923748.gif
Why Is It Important?
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2008: 182,460 (female); 1,990 (male) have
breast cancer
Deaths: 40,480 (female); 450 (male)
"The overall cost for treating a typical breast
cancer will top $50,000 or even $100,000." Dr. Stephen Edge
http://www.cancer.gov/cancertopics/types/breast
What’s The Focus?
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Research and have an understanding of how
cells develop into cancer cells
To build a model representing the protein
Have a better understanding on the
treatments given to patients
Cure?
Students Modeling A Research Topic
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Group of students
Explore science as
a process, not facts
Model protein of
study
Presentations
Why Join SMART Team?
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Looking for Honors Work as LEAP students
Topic: Cancer (Mainly breast cancer)
Looked easy
Extremely difficult
Engaged our knowledge
Do you have to
be smart?
Students Part of SMART Team
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Group 1: Kaoley Vue, KaoSong Xiong,
Mitchell Asplund, Ching Vang, Derek Unrau
Group 2: Shaenah Maguire, Erin Lawrence,
Jim Slogar, Samuel Joswiak
Group 3: Colton Cummings, Thomas Fish,
Addela Marzofka, Brady Sebo
Leukemia cancer cells
Cancer: What is it?
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Organs made of cells
Cells divide & multiply when our body need
them
Keeps dividing; too much
Result is a mass or growth; tumor
Can be benign or malignant
Common Types of Cancer
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Breast Cancer
Leukemia
Lung Cancer
Pancreatic Cancer
Breast cancer cell
www.hopeforcancer.com/images/BreastCancerCell.jpg
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Kidney Cancer
Bladder Cancer
Thyroid Cancer
Prostate Cancer
Prostate cancer cell.
Lung cancer cell dividing.
http://www.sanger.ac.uk/Info/Press/gfx/070307_lung-cancer-cells_300.jpg
http://www.chemlin.net/news/2006/sep2006/images/prostate-cancer-cell.jpg
http://www.cancer.gov/cancertopics/commoncancers
It’s Causes
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About 200 different
types
No single cause for
any one type
Multifactorial
Carcinogen
Age
Genetic make up
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Immune systems
Viruses
Day to day environment
(smoke, sun, manmade
radiation, etc.)
Bacterial infections
http://www.cancerhelp.org.uk/help/default.asp?page=119#multi_fact
http://www.nlm.nih.gov/MEDLINEPLUS/ency/images/ency/fullsize/18013.jpg
Controlling Cancer
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Chemotherapy
Radiation Therapy
Hormonal Therapy
Targeted Therapy (Our Main Focus)
Biological Therapy
http://patient.cancerconsultants.com/CancerTreatment.aspx
http://graphics8.nytimes.com/images/2007/08/01/health/adam/9805.jpg
How Does This Happen?
 Firefighters, police,
investigators…
 “first messenger,”
dispatcher “receptor,”
firefighters “second
messengers.”
Communication
is the key to
success.
One Particular Focus…
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Main Focus: Tyrosine receptor kinase (RTK)
Caused by uncontrolled and inaccurate
communication between cells
High affinity cell surface receptor
Critical role in developing and progression of
cancers
What is Tyrosine Receptor
Kinase and ATP?
Let Me Take
These!
 Multifunctional
nucleotide
 Plays an
important role in
cell biology as a
coenzyme
ATP
Tyrosine Kinase: What Is It? Ask
Me
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Enzyme: Transfers phosphate group
from ATP (Adenosine triphospate) to
tyrosine residue in a protein
Phosphorylation - the addition of a phosphate (PO4)
group to a protein or other organic molecule.
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Cascade of events; transmit the
extracellular signal to nucleus
Gene changes
Result: A hyper-active receptor
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Dr. Stanley Cohen (Biochemist)
Produced by cell and transported to the
membrane
Enabled scientists to further explore the cell
growth process
Certain cells have this
Highly concentrated
Used in cells that are epidermal in nature
http://www.nndb.com/people/687/000132291/stanley-cohen.jpg
EGF Background
Why is EGF produced?
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Regulate cell division
Needs to be a way to regulate
Hey! It DOES look
like a mouse!
Rainbow colored NMR
structure of the mouse
epidermal growth factor
http://en.wikipedia.org/wiki/Epidermal_growth_factor#cite_note-pmid10082370-0
EGFR
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Cell-Surface Receptor
Member of the ErbB
family
Attached to the cell's
plasma membrane
Regulate cell division
Involved in breast
cancer, lung cancer,
and more
http://discover8.com/public/images/upload_article_images/egf.jpg
Pathways
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The RAS/ERK pathway
PI3 Kinase/AKT pathway
JAK/STAT pathway
RAS/ERK: Promotes cell division
PI3 Kinase/AKT: Cell survival
JAK/STAT: Regulation of cellular responses
to cytokines and growth factors
http://www.abcam.com/index.html?pageconfig=resource&rid
=10723&pid=10628
RAS/ERK Pathway
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EGF activates EGFR
Binding Grb2 or Shc to
phosphorylated ErbB
Recruits SOS (son of
sevenless)
SOS activates RAS
activates RAF-1
So on and so forth until
cell divides
Activation of EGFR
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Dimerization: Chemical or biological entity
(consists of 2 monomers)
Held together by intramolecular forces or
weaker intermolecular forces
Hangs out on membrane as monomer
Needs dimerization to enable the auto-transphosphorylation
Phosphorylates other monomer
But, before I go…what
does this picture mean
again?
Carcinogenesis: How It Happens
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Stage 1: INITIATION
* Mistakes when DNA is copied from one cell to another
* Introduces a genetic error to the cell’s offspring
* Can happen spontaneously or be inherited
* Genes usually fix it; if can’t, suicide
* If gene’s damaged, defense mechanism lost
Stage 2: PROMOTION
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http://www.empowher.com/media/reference/kidney-cancer
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Mutation leads to mutation =
Cancer
Starts promoting cell growth when
restricted
Multiplies uncontrollably
Genes that control cell death
become altered; no suicide
Damaged cell continue to
reproduce; passing on mistakes
Advantage; acquire additional
genetic changes
Stage 3: PROGRESSION
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zZzzZ….
Tumors have a life of their own
Need blood and oxygen to survive
Develops own blood vessels that connect to body
Possible to spread through body
Breaks loose from original tumor and floats
through bloodstream to other parts of the body
where they attach themselves to healthy tissues
Invade normal tissues, new blood vessels,
overgrow normal tissues
Stage 3: PROGRESSION
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http://www.themesotheliomalibrary.com/tnm-staging.jpg
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Tumors have a life of their own
Need blood and oxygen to survive
Develops own blood vessels that
connect to body
Possible to spread through body
Breaks loose from original tumor
and floats through bloodstream to
other parts of the body where they
attach themselves to healthy
tissues
Invade normal tissues, new blood
vessels, overgrow normal tissues
Stage 3: Progression Continued
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Have more mutations than the cells in
original tumor
Spreading cancer harder to kill
More deadly than the original
New tumors acquire more changes to resist
effective treatment
http://www2.mdanderson.org/depts/oncolog/articles/04/9-sep/9-04-hc.html
Movie To Explain
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Part 1 and 2: A Clearer Understanding
Hmmmm…so
How Do We Control/Get Rid of It?
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Removal of tumor
 Chemotherapies
(drugs that can kill cancer cells)
 Radiation therapies
 Drugs
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Control/Get Rid of Cancer
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Hormone Therapy: An approach that
controls/blocks hormones’ ability to
promote tumor growth.
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Biological Therapy: Takes advantage of
body's own immune or hormonal system to
act on cancer cells - while leaving healthy
cells intact
Control/Get Rid of Cancer Continued
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Targeted Therapy: Medication that blocks
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the growth of cancer cells
Interferes with specific targeted molecules
needed for carcinogenesis and tumor growth
Our SMART Team’s Job
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Illustrate modeling effectiveness in combating
cancer
In the process show
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How a drug inhibits EGFR
Another potential site to stop uncontrolled cell
division
Background Knowledge
First purified protein gets
crystallized
Calcium protein crystallized
http://www.laurentian.ca/Laurentian/Home/Departments/Behavioural+Neuroscience/Pictures/Histology.htm?imgidx=3&Laurentian_Lang=en-CA
X-ray Crystallography
 Bombard a crystallized sample with
X-rays
 Leaves an “image”
•http://upload.wikimedia.org/wikipedia/en/thumb/e/e3/X-ray_crystallography.svg/691px-X-ray_crystallography.svg.png
Steps in
Determining a
Protein’s Structure
Using X-Ray
Crystallography
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 X-ray
Data
Epidermal Growth Factor Receptor
Space filled model of
EGFR
Epidermal Growth Factor Receptor
Backbone structure of EGFR
EGFR With And Without
Drug Lapatinib
Lapatinib: Two different models
of the atom structure
EGFR
GW572016 (Lapatinib)
OSI-774 (Tarceva)
ZD-1839 (Iressa)
https://www.tykerb.com/images/tykerb-logo.jpg
http://www.pharmacyrxworld.com/productimages/iressa.jpg
http://www.roche.co.nz/images/logos/46.jpg
Drugs that Inhibit Clinical Development
The Drug
The K-value
(Tendency to grab onto EGFR)
Our drug GW572016
(Lapatinib)
3.0
OSI-774 (Tarceva)
0.4
ZD-1839 (Iressa)
0.7
RAS/ERK Pathway
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EGF activates EGFR
Binding Grb2 or Shc to
phosphorylated ErbB
Recruits SOS (son of
sevenless)
SOS activates RAS
activates RAF-1
So on and so forth until cell
divides
RAS
Another Site to Interfere with Cancer
Progression
RAS: The Active Site
RAS: The Active Site Side
View And Profile
RAS: The Active Site & The Groove
Spot of great interest
Overall Cancer Views
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Still much to learn for cancer
drugs
Of course there’s much to
Cure?
learn; you’re no expert or
Treatment may not be
scientist!
success
Blocked pathway = a new
route for cancer cells
Tumors: shrink, pores shrink
(blood vessels around);
larger molecules in drug are
ineffective
Overall Cancer Views Continued
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Better characterization of patients in trials
Tumors: biopsied & characterized on
molecular and cellular level
Chance of relapse
Acknowledgements
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Dr. Shannon Colton
All of the people of the Center for
Biomolecular Modeling at the Milwaukee
School of Engineering
Mr. Heeren