Transcript Cancer Bioinformatics

GENETICS OF CANCER
Michael Sheets
Topics in
Bioengineering
Fall 2014
INHERITED CANCER?
 Doctors noticed a while back (i.e. ancient Greece 5 ) that some
cancers run in families
 Could be similar environment – smoking, food, radiation
 But appeared to have more to it
McPherson et al, 2000.
FAMILY CANCER SYNDROMES
 Along came the HGP and huge advances in genetics…
Associated Gene
Familial retinoblastoma
RB1
Li-Fraumeni
TP53
Familial adenomatous polyposis
APC
Hereditary nonpolyposis
colorectal cancer
MLH1,2,6
PMS1,2
Wilms’ tumor
WT1
Breast and ovarian cancer
BRCA1,2
Von Hippel-Lindau
VHL
Cowden
PTEN
 Individuals can be tested for related genes
National Cancer Institute.
Retrieved from http://www.webbooks.com/eLibrary/ON/B0/B10/41MB10.html
Syndrome
BENEFITS OF KNOWING

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Generally more screening: caught earlier
Lifestyle changes to help prevent it
Af fect prognosis & treatment if cancer occurs
Can pass info on to family – may be af fected as well
Bode & Dong, 2009.
GENETIC TREATMENT OF CANCERS
 Once related genes are found, often look for why they cause
increased likelihood
 Can use this info to craft new ways of treating cancers 2
 Specific drugs to target proteins made by mutated genes
 HER2 oncogene – trastuzumab (Herceptin®), lapatinib (Tykerb®) to
attack HER2 positive cells
 BCR-ABL – target products to prevent chronic myeloid leukemia
 Reactivate methylated (turned off) genes
 hypomethylating agents, ie decitabine (Dacogen®)
 Test if a drug will work
 Some drugs don’t work
BRCA (TIMELINE)
1800s: ‘Latent state’ BC
1920s: More likely to die of BC if
your mother did
1990: Correlation discovered
between 17q21 (10x likelihood w/
mystery gene)
1994: BRCA1 discovered
1995: BRCA2 discovered
20??: BRCA3?
McPherson et al, 2000.
BRCA (ISOLATION)
King, 2014.
BRCA (FUNCTION)
INTERESTING ETHICS
 Gene patents (2013)
 No for natural
 Yes for artificial
 Genetic Discrimination
 By insurance agencies/
employers
 Led to…
 Genetic Information
Nondiscrimination Act
(2008)
Holman C. (2008). Science 322:198-99. Retrieved from
http://www.patentdocs.org/2008/12/science-articleshould-help-allay-fears-concerning-gene-patents.html
REFERENCES
1. Bode A. M. & Dong Z. (2009). Cancer prevention research -then and now. Nat Rev Cancer 9(7)508-16.
2. Genetics and Cancer. (2014). Retrieved from
http://www.cancer.org/cancer/cancercauses/geneticsandcancer/index
3. Genetic information Nondiscrimination Act of 2008. (2014) Retrieved from
http://www.genome.gov/10002328
4. Hall J. M. et al. (1990). Linkage of early -onset familial breast cancer to chromosome 17q21. Science,
250(4998)1684-89.
5. King M-C. (2014). “The race” to clone BRCA1. Science, 343(1492)1462-65.
6. McPherson K. et al. (2000). Breast cancer —epidemiology, risk factors, and genetics. British Medical
Journal, 321(7261)624-8.
7. Than K. (2013). Takeaways from the Supreme Court’s gene patent decision. National Geographic.
Cancer Immunology
-The relationship between cancer and the immune system-
Inseong Joe
What is Cancer Immunology?
Why Cancer Immunology?
The Connection
Immunoediting
: Process by which a person is protected from cancer
growth and development of tumor immunogenicity by
their immune system
Elimination
Equilibrium
Escape
Elimination
Phase 1
• Initiation of antitumor immune response
• Induction of inflammatory signals
Phase 2
• IFN-gamma induces tumor death + promotes production of chemokines
• Recruitment of more immune cells
Phase 3
• Natural killer cells & macrophages transactivate one another
• More tumor death via apoptosis
Phase 4
• Tumor-specific T cells at tumor site and cytolytic T lymphocytes destroy
antigen-bearing tumor cells remaining
Equilibrium and Escape
• Equilibrium Phase
: Lymphocytes and IFN-gamma exert selection
pressure on tumor cells
• Escape Phase
: Tumor cells continue to grow and expand
Tumor Immunotherapy
• Patient’s immune system stimulated to fight
tumors
Nonspecific
Immunotherapy
Antigen-specific
Immunotherapy
Nonspecific Immunotherapy
• Bacile Calmette-Guerin (BCG) therapy
– Administration of weakened forms of
mycobacterial strain
– Probably activates macrophages and lymphocytes
• Cytokines
– Direct antitumor effect
– Indirect enhancement of antitumor immune
response
• Cell therapy
– Transfer of live, whole cells into patients
Specific Immunotherapy
Adoptive
Transfer
Vaccination
Adoptive Transfer
• All therapies that consist of transfer of
components of immune system already
capable of mounting immune response
• Antibody Therapy
• Adoptive transfer of T cells
Vaccination
• Place antigen within patient so that immune
systems can be provoked to unleash killer T
cells
• Design antigens that selectively activate
specific T cells to kill cancer cells
• Success depends on
– Mode of antigen delivery
– Choice of adjuvant
– Particular antigen
cervical cancer + HPV
Paige Cote
HPV
● More than 150 types of virus, ~40 that are
easily spread. >50% of sexualy active
individuals
● Types 16 and 18 (high risk) are responsible
for most cervical cancers
● Most high risk infections go away within 1-2
years
HPV and Cancer
● Can cause cervical, anal, vaginal, vulvar,
and penile cancers. Plus the cancer of the
oropharynx.
● Cancer more likely when combined with
certain risk factors
● Prevent with abstinence or vaccines
● Testing only available for women
How?
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●
●
●
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Epithelial Cells
Proteins
Time
High grade lesions
Other factors in your health
This is what it looks like, sorry!
Removal
CANCER
BIOINFORMATICS
Shrinidhi Thirumalai
Why Bioinformatics?
Problem: High Variation in Cancer:
• Severites, Resistance, Origins,
Genes, environment etc.
• Makes it extremely hard to quantitatively assess specific
treatments
Why Bioinformatics?
Solution: Systems Clinical Medicine with
Bioinformatics as a tool
• Iterative process between:
• data-driven computational and mathematical models
• model-driven translational and clinical investigations.
• Takes a variety of factors such as environment and
genes into account
Applications
• Personalized Medicine
• Pharmaceutical drug/vaccine development
• production, delivery and safety
• Ex: Most optimum patient groups to focus on first
• Discovery of biomarkers
• effective diagnosis
• Design of combinatorial therapies
• Ex: Dosing and administration patterns
Biomarkers
• Phenotypes related to early diagnoses
• measurements to monitor progress of disease
• measurements to monitor response to therapy
• predictors for the improvement of life quality
Network Biomarkers
• Set of biomarkers and their
interactions
• Analyze gene or protein
expression data and other highdimensional profile data with over
thousands of measurements
• Achieved higher accuracy
• Dynamic Biomarkers: connect to
clinical informatics as well (patient
complaints, histories, etc)
Molecular
Markers of
Cancer
Anna Knapp
Biomarkers
• Can be almost any type of molecule
• Protein, nucleic acids, antibodies,
peptides etc…
• Can also be a change in a group of
things – gene expression, metabolic
signatures, etc…
• Detection is non-invasive
From Wikipedia
Lynn Henry et. Al.
Detection
Techniques
• Assays
• Used to detect the
presence of a small
number of markers
o Proteins often measured using
standard antibody testing
• Protein profiling – Higher
throughput methods of
detecting and quantifying
multiple Biomarkers
o Mass Spec
o Chromatography
o surface-enhanced laser
desorption/ionization
• QRT-PCR
o Used to measure gene expression
o Faster than microarrays
Felix Kinger
 Hyperthermia
= body temperature that is
higher than normal
 Can be used to make other treatments more
effective
 Can kill cancer cells outright
(but also normal cells and tissue!)
 Local
hyperthermia (high heat):
very high temperatures to destroy a small
area of cells
 Two
1)
2)
ways of application
External:
High energy waves are aimed at tumor
from outside the body
Internal:
A thin needle or probe is put right into
the tumor and releases energy
 Microwaves
 Ultrasound
waves
 Radiofrequency ablation (RFA)
-> high energy radio waves
-> internal application
-> creates heat between 122-212F
-> most effective for liver, kidney, lung
cancer
 Regional
hyperthermia (low heat):
temperature of a part of the body is raised
by a few degrees higher then normal
 Supportive
treatment
effect, combined with other
Regional perfusion
->
->
->
->
->
Blood supply from part of the body is
isolated
Blood goes into heating device and back
to the body
Chemotherapy may be applied at the
same time
Temperature ranges from 104F to 113F
Mostly to treat cancer in arms and legs
 Mostly
used against metastatic cancer
 Heating
blankets
 Warm water immersion
 Thermal chambers
 Temperature around ‘fever-level’ (100F)
PROS
CONS
- Can destroy tumors without
surgery
- Can be combined with other
treatment methods
- Holds potential in the future
- experimental technique
- Requires special and not
easily accessible equipment
- Can cause damage to skin,
muscles and nerves near the
treated area
 http://www.cancer.org/treatment/treatmen
tsandsideeffects/treatmenttypes/hyperther
mia
 http://www.cancer.gov/cancertopics/factsh
eet/Therapy/hyperthermia
 http://www.wjgnet.com/1948-
5204/full/v3/i12/WJGO-3-169-g001.jpg
Laser Treatment for
Cancer
Kevin Suzuki
What is Laser Treatment
● Lasers are used to burn away abnormal or
cancerous cells in a process known as laser
ablation
Methods of Using Lasers
1. Laser can shrink or destroy tumor with heat
2. Laser can activate a chemical
(photosensitizing agent) that kills only the
cancer cells
Types of Lasers
-CO2 lasers: can cut or vaporize tissue with
little bleeding and is used to remove thin layers
from surface
-Argon lasers: Treat skin problems and eye
surgeries and is used in photodynamic therapy
-Neodymium: Yttrium-Aluminum-Garnet Lasers:
used for hard to get places like esophagus and
is much stronger
What Cancers is this Applicable to?
● Used for precancerous changes and cancers on the
surface of body like basal cell skin cancer
(Photodynamic Therapy)
● Cervical cancer, Penile cancer, Vaginal cancer, Vulval
cancer and melanoma of the eye
● Some internal organs like oesophagus and trachea and
early stages of non small cell lung cancer (85-90%)
Photodynamic Therapy
● Phototherapy using non
toxic light-sensitive
compounds that are
exposed selectively to
light where they become
toxic to targeted
malignant and other
diseased cells
Photodynamic Therapy Continued
3 Key components to success
1. Photosensitizer is excited from
2. Light Source which produces
3. Oxygen which is reactive and actively
attacks any organic compounds it
encounters
Advantages of Photodynamic Therapy
- Cancer cells can be singled out and
destroyed
- Damaging effect of photosensitizing agent
happens only when drug is exposed to light
- Mild side effects
Cons of Photodynamic Therapy
- Laser cannot hit deep tumors
- Photosensitizing agents can leave people
very sensitive to light, causing sunburn- like
reactions after very brief sun exposure
Laser Therapy for Cervix, Vagina or Vulva
● Goal: Doctor uses laser to burn away
abnormal cells
● Steps: 1) Doctor puts a speculum into vagina
and holds it open and puts anaesthetic onto
cervix and vaginal wall to numb it
● 2) Points laser at abnormal area where laser
burns away abnormal tissues
Laser Therapy for Penile Cancer
● Used for only early cancer of penis
● Steps: 1) Doctor puts anaesthetic on penis
● 2) Doctor uses powerful beam that acts like
a knife which cuts away tumor but doesn’t go
deep into tissue
Laser Therapy for Cancer in Body
(Endoscopic Resection)
● Goal: Laser cuts and burns away cancerous
tissue
● Ex. Lung cancer: 1) Doctor uses
bronchoscopy to position laser and tube has
a light at end and an eyepiece so doctor can
see any abnormal areas
● 2) Doctor positions end of tube close to
tumor and laser cuts cancerous tissue
Laser Treatment of Esophagus
Advantages:
● Seals off blood vessels as it cuts so
minimizes bleeding
● Lasers are more precise than blades
● Heat produced by laser sterilizes edges of
body tissue it is cutting
● Operating time is shorter
● Healing time is often shorter
Cons of Laser Surgery
Few doctors know how to use lasers
Very expensive and bulky
Strict safety precautions must be followed
Effects may not last as long so some treatment
may have to be repeated
Works Cited
http://www.cancer.org/cancer/lungcancer-nonsmallcell/detailedguide/non-small-cell-lung-cancer-what-isnon-small-cell-lung-cancer
http://www.cancerresearchuk.org/about-cancer/cancers-ingeneral/treatment/other/laser-treatment
http://www.cancer.org/treatment/treatmentsandsideeffects/t
reatmenttypes/lasers-in-cancer-treatment
Photodynamic therapy
• Phototherapy using
nontoxic light
sensitive chemicals
called
Photosensitizing
agents
Photodynamic Therapy
• Photosensitizing agents
applied to skin or in the
blood
• 24-72 hours later agents
has left normal cells but
remain in tumors
• Large tumors may
shrink but not be
destroyed
Photodynamic Therapy
•
•
•
•
•
•
Outpatient Procedure
Less invasive
Repeatable
Used with other therapies
No scar tissue
Even used outside the
body Extracorporeal
photopheresis (ECP) for
cancers that affect blood
• No long term side affects
Photodynamic Therapy
•
•
•
•
•
Several short term side affects
Light can’t penetrate more than about 1 cm
Can’t break down large tumors
Can’t treat metastasized tumors
People who have certain blood diseases or allergies
to porphyrins cannot undergo PDT
Photodynamic Therapy