Cancer: Modeling Different Methods to Control It A SMART Team Project

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Cancer Modeling Different Methods to Control It
A SMART Team Project

• By Kaoley Vue, KaoSong Xiong, Mitchell Asplund,
  Ching Vang, Derek Unrau

Im coming along, too!
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Why Is It Important?
http//media-2.web.britannica.com/eb-media/15/6771
5-004-AD923748.gif

• 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

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Whats The Focus?

• 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?

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Students Modeling A Research Topic

• Group of students
• Explore science as a process, not facts
• Model protein of study
• Presentations

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Why Join SMART Team?

• 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?
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Students Part of SMART Team

• 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

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Cancer What is it?
Leukemia cancer cells

• 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

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Common Types of Cancer

• Breast Cancer
• Leukemia
• Lung Cancer
• Pancreatic Cancer

• Kidney Cancer
• Bladder Cancer
• Thyroid Cancer
• Prostate Cancer

Breast cancer cell
Lung cancer cell dividing.
Prostate cancer cell.
www.hopeforcancer.com/images/BreastCancerCell.jpg
http//www.sanger.ac.uk/Info/Press/gfx/070307_lung
-cancer-cells_300.jpg
http//www.chemlin.net/news/2006/sep2006/images/pr
ostate-cancer-cell.jpg

• http//www.cancer.gov/cancertopics/commoncancers

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Its Causes

• About 200 different types
• No single cause for any one type
• Multifactorial
• Carcinogen
• Age
• Genetic make up

• Immune systems
• Viruses
• Day to day environment (smoke, sun, manmade
  radiation, etc.)
• Bacterial infections

• http//www.cancerhelp.org.uk/help/default.asp?page
  119multi_fact

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Controlling Cancer
http//www.nlm.nih.gov/MEDLINEPLUS/ency/images/enc
y/fullsize/18013.jpg

• Chemotherapy
• Radiation Therapy
• Hormonal Therapy
• Targeted Therapy (Our Main Focus)
• Biological Therapy

• http//patient.cancerconsultants.com/CancerTreatme
  nt.aspx

http//graphics8.nytimes.com/images/2007/08/01/hea
lth/adam/9805.jpg
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How Does This Happen?

• Firefighters, police, investigators
• first messenger, dispatcher receptor,
  firefighters second messengers.

Communication is the key to success.
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One Particular Focus

• 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

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What is Tyrosine Receptor Kinase and ATP?
Let Me Take These!

• Multifunctional nucleotide
• Plays an important role in cell biology as a
  coenzyme

ATP
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Tyrosine Kinase What Is It? Ask Me

• 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.
• Cascade of events transmit the extracellular
  signal to nucleus
• Gene changes
• Result A hyper-active receptor

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EGF Background
http//www.nndb.com/people/687/000132291/stanley-c
ohen.jpg

• 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

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Why is EGF produced?

• 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_fact
orcite_note-pmid10082370-0
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EGFR

• 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
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Pathways

• 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?pageconfigresourc
  erid10723pid10628

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RAS/ERK Pathway

• 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

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Im gonna go take a nap.
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Activation of EGFR

• 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-trans-phosphorylation
• Phosphorylates other monomer

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But, before I gowhat does this picture mean
again?
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Carcinogenesis How It Happens

• Stage 1 INITIATION
• Mistakes when DNA is copied from one cell
  to another
• Introduces a genetic error to the cells
  offspring
• Can happen spontaneously or be inherited
• Genes usually fix it if cant, suicide
• If genes damaged, defense mechanism lost

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Stage 2 PROMOTION

• 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

http//www.empowher.com/media/reference/kidney-can
cer
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Stage 3 PROGRESSION
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

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Stage 3 PROGRESSION

• 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

http//www.themesotheliomalibrary.com/tnm-staging.
jpg
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Stage 3 Progression Continued

• 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

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Movie To Explain

• Part 1 and 2 A Clearer Understanding

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How Do We Control/Get Rid of It?
Hmmmmso
?
?
?

• Removal of tumor
• Chemotherapies
• (drugs that can kill cancer cells)
• Radiation therapies
• Drugs

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Control/Get Rid of Cancer

• Hormone Therapy An approach that controls/blocks
  hormones ability to promote tumor growth.
• Biological Therapy Takes advantage of body's own
  immune or hormonal system to act on cancer cells
  - while leaving healthy cells intact

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Control/Get Rid of Cancer Continued

• Targeted Therapy Medication that blocks the
  growth of cancer cells
• Interferes with specific targeted molecules
  needed for carcinogenesis and tumor growth

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Our SMART Teams Job

• Illustrate modeling effectiveness in combating
  cancer
• In the process show
• How a drug inhibits EGFR
• Another potential site to stop uncontrolled cell
  division

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Background Knowledge
First purified protein gets crystallized
Calcium protein crystallized
http//www.laurentian.ca/Laurentian/Home/Departmen
ts/BehaviouralNeuroscience/Pictures/Histology.htm
?imgidx3Laurentian_Langen-CA
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X-ray Crystallography

• Bombard a crystallized sample with X-rays
• Leaves an image

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

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Steps in Determining a Proteins Structure Using
X-Ray Crystallography
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 X-ray Data
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Epidermal Growth Factor Receptor
Space filled model of EGFR
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Epidermal Growth Factor Receptor
Backbone structure of EGFR
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EGFR With And Without Drug Lapatinib
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Lapatinib Two different models of the atom
structure
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EGFR
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Drugs that Inhibit Clinical Development
GW572016 (Lapatinib)
http//www.roche.co.nz/images/logos/46.jpg
OSI-774 (Tarceva)
ZD-1839 (Iressa)
https//www.tykerb.com/images/tykerb-logo.jpg
http//www.pharmacyrxworld.com/productimages/iress
a.jpg
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RAS/ERK Pathway

• 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

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RAS
Another Site to Interfere with Cancer Progression
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RAS The Active Site
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RAS The Active Site Side View And Profile
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RAS The Active Site The Groove
Spot of great interest
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Overall Cancer Views

• Still much to learn for cancer drugs
• Cure?
• Treatment may not be success
• Blocked pathway a new route for cancer cells
• Tumors shrink, pores shrink (blood vessels
  around) larger molecules in drug are ineffective

Of course theres much to learn youre no expert
or scientist!
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Overall Cancer Views Continued

• Better characterization of patients in trials
• Tumors biopsied characterized on molecular and
  cellular level
• Chance of relapse

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Acknowledgements

• Dr. Shannon Colton
• All of the people of the Center for Biomolecular
  Modeling at the Milwaukee School of Engineering
• Mr. Heeren