Week 4 - Personalized Medicine

Question 1

What factors influence how a person responds to medicine?

Answer 1

Genetics* Weight Diet Food in stomach Fatigue Age Sun exposure Physical condition / lack of exercise Drug interactions (i.e., Cross reactivity, synergism) Genetic make-up** Comorbidities

Question 2

Cancer pt drugs are now starting to be decide on…

Answer 2

Their genome. They do genetic tests to find out which drugs will work the best

Question 3

What are three main categories of drug reactions?

Answer 3

1. drug-metabolizing enzymes (influence pharmacokinetics) Poor clearance of drugs may increase to toxic levels An example is thiopurine -S -methyltransferase 2. Drug transporters (influence pharmacodynamics) (some ppls transporters may be more efficient) 3. HLAs (human leukocyte antigen) drug sensitivities may look like an allergy (sensitivities to diff drugs differ in ppl)

Question 4

Goals of personalized medicine

Answer 4

Safer Drugs (less side effects)

Increased Drug effectiveness (so ppl don’t have to take as much = saved money)

Alternative drugs for ‘standard treatments’

Dosages’s based on an individuals genetics

More effective and safer (warfarin example)

Question 5

Warfarin

Answer 5

Most common anticoagulant prescribed in N. America

Used to prevent blood clots

Prescribed for ppl who have:

• certain types of irregular heart beat
• prosthetic valves
• have had a MI

Question 6

Warfarins effects on food:

These affect how warfarin functions

Answer 6

Diet low in Vitamin K

Avoid large amounts of kale, spinach, brussels sprouts, parsley, collard greens, chard, green tea

Avoid beverages: Cranberry juice, alcohol

Question 7

Warfarin:

Genetics

Ethnicity

Foods

Alcohol

Drug-Drug interactions

Answer 7

Genetics. Variants in both vitamin K epoxide reductase (VKORC1) and cytochrome p450 2C9 (CYP2C9) have a significant impact on warfarin sensitivity. Carriers of specific variations may be more sensitive to warfarin and may therefore require significantly lower doses than those with other variations. Variations in VKORC1 have a much greater impact on warfarin sensitivity than variations in CYP2C9, particularly during the initiation of therapy.

Ethnicity. There are significant differences in warfarin dose requirements among different ethnic groups. Specifically, it has been recognized that people of East Asian descent require on average a 30-40% lower warfarin dose than individuals of European descent. In recent years it has become apparent that the VKORC1 gene variants that are associated with lower warfarin doses are much more common in Asians than Europeans, explaining most, if not all, of the difference attributable to ancestry.

Foods high in vitamin K. Vitamin K is a natural blood-clotting factor and can reverse the blood-thinning effects of warfarin. Broccoli, lettuce, spinach and liver are all high in vitamin K. It is not recommended to eliminate these foods from the diet when taking warfarin, but to eat them in consistent amounts so as to maintain a balance with respect to warfarin dosing.
Alcohol. Excessive use of alcohol is also known to affect the metabolism of warfarin and can increase its blood-thinning effects.

Interaction with other medications. Many medications interact with warfarin, affecting its anticoagulation activity, including aspirin, some antibiotics and birth control pills. Warfarin also interacts with many herbal remedies.

Question 8

Warfarin:

Main points

Answer 8

Genetics. Variants in both vitamin K epoxide reductase (VKORC1) and cytochrome p450 2C9 (CYP2C9) have a significant impact on warfarin sensitivity.

Ethnicity. There are significant differences in warfarin dose requirements among different ethnic groups.
Other interactions….

Question 9

What is 23 and Me?

Answer 9

Genetic Testing…

Question 10

Warfarin is an example of personalized medicine… What are the take home points?

Answer 10

• Do not guess at ethnicity (people are 99.9% the same genetically)
• Do not guess at genetic alleles (test for them)
• It is possible to test for genetic alterations leading to variable drug response.

Question 11

Only ____% of genome is used as coding sequences for proteins?

Answer 11

2%

Question 12

How many base pairs of DNA are in human genome?

How many differ throughout the genome?

Answer 12

• 3 billion base pairs of DNA in our genome
• 3 million base pairs differ throughout the genome (3,000,000,000 X 0.001 = 3,000,000 base pairs / or 3 million)

Question 13

How many differances are there in noncoding RNA?

Answer 13

Differences in noncoding RNAs could be as much as 2.94 million individual SNPs.

SNP - Single nucleotide polymorphism

Question 14

What is a SNP?

Whys is it important?

Answer 14

• Single Nucleotide Polymorphism - Naturally occuring varitation in (base pair) DNA sequence. The encoded proteins function may or may not be altered.
• Getting away from “one size fits all” drugs.
• We all have different polymorphisms.
• Personalized medicine seeks to use our understanding of SNPs and other genetic info to improve patient outcome

Question 15

How to detect SNP?

Answer 15

• Deep Sequencing - Rapidly increasing - can go look at specific areas of genomes and can narrow it down. Can take a week.
• Exon trapping (not really used much)
• Direct sequencing - This is by far the most common - can take 2 weeks..

Question 16

Direct Sequencing…

Answer 16

If have G instead of T (mutation). Then a certain cancer drug will be more effective if pt HAS this mutation

Direct sequencing will tell if this pt has this mutation so they can be treated

Question 17

Definition of pharmacogenetics (pharmacogenomics)

Answer 17

• The study of how an individual’s genetic inheritance affects the body’s response to drugs.
• … decoding drug responsiveness
• … the development of genetic tests that will tell doctors which people should get which drugs, to maximize drug effectiveness and minimize side effects

Question 18

Pharmacogenomics

Answer 18

Pharmacology + genomics = the intersection of pharmaceuticals and genetics… decoding drug responsiveness
“Pharmacogenomics” includes the spectrum of genes that determine drug behavior and sensitivity

Question 19

What decisions will require pharmacogenetics?

Answer 19

• The proper diagnosis (new born screening)
• The proper treatment (BRAF testing) (must test pt prior to treatment or it will not work*)
• The prediction of outcome
• The prediction of drug response (KRAS) (Must test firs or drug response will be bad*)
• Selection of Alternative drugs that may improve outcome

Question 20

What is the goal of pharmecokinetics…

Answer 20

• The goal is to have:
• Safer drugs (reduction of side effects)
• Increased drug effectiveness
• Alternative drugs for “standard treatments”
• Dosages based on an individual’s ability to metabolize
• More effective thereby reducing cost

Question 21

SNP

Difference in A or G in ppl

Answer 21

Question 22

What is the outcome Pharmacogetics (and human genome project)

Answer 22

• An outcome of the Human Genome Project.
• Study the genetics of drug metabolism.
• Single Nucleotide Polymorphisms (SNP) to see how differently individuals respond to medications.
• Resulting in personalized medicine
• Now drug companies must list the certain genotypes that the drug might effect (they will list gene names)

Question 23

Childhood Leukemia Example…

Answer 23

Note: American Indian children have the poorest survival from leukemia in comparison with children of other races

Childhood cancer is successfully treated by 6-mercaptopurine

“Successful” means more than 80% respond

BUT … that drug can be fatal in about 10% of children who could have been tested for a genetic alteration.

The genetic alteration prevents the metabolism of that drug.

Those unresponsive children can be given an alternative treatment that is not the “drug of choice” but is effective.

These children overdose on even small doses of 6-mercaptopurine

Question 24

What are some possible benifits from Pharmacogenetics?

Answer 24

• Reduce or eliminate side effects from medications
• Access “designer” drugs
• Increase effectiveness of treatments
• More effective and efficient treatments tailored to the individual
• Of those individuals who metabolize a drug too quickly to benefit from any effect
• Like Codeine
• Some people currently are erroneously labeled “drug addicts” because they request additional pain killers
• Medical staff erroneously thinks the patient has high tolerance (maybe they have a genetic mutation that metabolizes the drug very quickley…)
• With personalized medicine, such mislabeling would be less common

Question 25

Possible drawbacks to community members from Pharmacogenetics?

Answer 25

• Drug companies may limit their testing to specific groups excluding poorer populations.
• People are worried that their genetic profiles will fall into the wrong hands

Question 26

How can such concerns about human genomes be ethically addressed?

Answer 26

• More time spent with the patient explaining pharmacogenetics.
• Better understanding among physicians about genetics and the influence of various alleles on treatment

CASE: Experience with Medical Oncology Fellow

• Assuming drug abuse
• Cultural competency needs improvement

Question 27

Objectives

Answer 27

Students will be able to identify 3 benefits of personalized medicine

Students will be able to identify selected alleles which should be examined prior to prescription of warfarin

Students will be able to describe molecular tests that maybe used for detecting genetic variants ( SNPs)