Michael SheetsTopics in Bioengineering Fall 2014

GENETICS OF 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

INHERITED CANCER?

McPherson et al, 2000.

Along came the HGP and huge advances in genetics…

Individuals can be tested for related genes

FAMILY CANCER SYNDROMES

Syndrome Associated Gene

Familial retinoblastoma RB1

Li-Fraumeni TP53

Familial adenomatous polyposis

APC

Hereditary nonpolyposis colorectal cancer

MLH1,2,6PMS1,2

Wilms’ tumor WT1

Breast and ovarian cancer

BRCA1,2

Von Hippel-Lindau VHL

Cowden PTEN

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Generally more screening: caught earlierLifestyle changes to help prevent itAff ect prognosis & treatment if cancer occursCan pass info on to family – may be aff ected as well

BENEFITS OF KNOWING

Bode & Dong, 2009.

Once related genes are found, often look for why they cause increased likelihood

Can use this info to craft new ways of treating cancers2

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

GENETIC TREATMENT OF CANCERS

BRCA (TIMELINE)

McPherson et al, 2000.

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?

BRCA (ISOLATION)

King, 2014.

BRCA (FUNCTION)

Gene patents (2013) No for natural Yes for artificial

INTERESTING ETHICS

Holman C. (2008). Science 322:198-99. Retrieved from http://www.patentdocs.org/2008/12/science-article-should-help-allay-fears-concerning-gene-patents.html

Genetic Discrimination By insurance agencies/

employers Led to… Genetic Information

Nondiscrimination Act (2008)

1. Bode A. M. & Dong Z . (2009) . Cancer prevent ion research- then and now. Nat Rev Cancer 9 (7 )508-16 .

2. Genet i cs and Cancer. (2014) . Ret r ieved f rom ht tp : / /www.cancer.org /cancer /cancercauses /genet i csandcancer / index

3. Genet i c in format ion Nond isc r im inat ion Ac t o f 2008 . (2014) Ret r ieved f rom ht tp : / /www.genome.gov/10002328

4. Ha l l J . M. e t a l . (1990) . L inkage o f ear ly- onset fami l i a l breast cancer to chromosome 17q21 . Sc ience , 250 (4998)1684-89 .

5. K ing M-C. (2014) . “The race” to c lone BRCA1. Sc ience , 343 (1492)1462-65 .6. McPherson K . e t a l . (2000) . Breast cancer—epidemio logy, r i sk fac tors , and genet i cs .

Br i t i sh Medica l Journa l , 321 (7261)624-8 .7. Than K . (2013) . Takeaways f rom the Supreme Cour t ’s gene patent dec i s ion . Nat iona l

Geograph ic .

REFERENCES

Cancer Immunology-The relationship between cancer and the immune system-

Inseong Joe

What is Cancer Immunology?

Why Cancer Immunology?

Immunoediting: Process by which a person is protected from cancer growth and development of tumor immunogenicity by their immune system

The Connection

Elimination Equilibrium Escape

EliminationPhase 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 destroyantigen-bearing tumor cells remaining

• Equilibrium Phase: Lymphocytes and IFN-gamma exert selection pressure on tumor cells

• Escape Phase: Tumor cells continue to grow and expand

Equilibrium and Escape

• Patient’s immune system stimulated to fight tumors

Tumor Immunotherapy

NonspecificImmunotherapy

Antigen-specificImmunotherapy

• 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

Nonspecific Immunotherapy

Specific Immunotherapy

AdoptiveTransfer Vaccination

• All therapies that consist of transfer of components of immune system already capable of mounting immune response

• Antibody Therapy• Adoptive transfer of T cells

Adoptive Transfer

• 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

Vaccination

cervical cancer + HPVPaige 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?

● Epithelial Cells● Proteins● Time● High grade lesions● Other factors in your health

This is what it looks like, sorry!

Removal

CANCER BIOINFORMATICSShrinidhi 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 high-dimensional 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

CancerAnna Knapp

Biomarkers

From Wikipedia

Lynn Henry et. Al.

• 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

DetectionTechniques

• Assays• Used to detect the presence

of a small number of markerso Proteins often measured using standard

antibody testing

• Protein profiling – Higher throughput methods of detecting and quantifying multiple Biomarkerso Mass Speco Chromatographyo surface-enhanced laser

desorption/ionization

• QRT-PCRo Used to measure gene expressiono Faster than microarrays

HYPERTHERMIA TO TREAT

CANCER

HYPERTHERMIA TO TREAT

CANCER

Felix Kinger

WHAT DOES IT MEAN? 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

Local hyperthermia (high heat):very high temperatures to destroy a small area of cells

Two ways of application1) External:

High energy waves are aimed at tumor from outside the body2) Internal:

A thin needle or probe is put right into the tumor and releases energy

HOW?

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

Regional hyperthermia (low heat):temperature of a part of the body is raised by a few degrees higher then normal

Supportive effect, combined with other treatment

HOW?

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

WHOLE BODY HYPERTHERMIA

Mostly used against metastatic cancer

Heating blankets Warm water immersion Thermal chambers Temperature around ‘fever-level’ (100F)

PROS & CONS

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/treatmentsandsideeffects/treatmenttypes/hyperthermia

http://www.cancer.gov/cancertopics/factsheet/Therapy/hyperthermia

http://www.wjgnet.com/1948-5204/full/v3/i12/WJGO-3-169-g001.jpg

Laser Treatment for CancerKevin 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 heat2. 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 produces3. 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 lasersVery expensive and bulky Strict safety precautions must be followedEffects may not last as long so some treatment may have to be repeated

Works Cited

http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-what-is-non-small-cell-lung-cancerhttp://www.cancerresearchuk.org/about-cancer/cancers-in-general/treatment/other/laser-treatment http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/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