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1
Overview of Pharmacogenomics
Faraza Javed
PhD Pharmacology
2
Pharmacogenomics
Pharmacogenomics is the study of how genes
affect a person’s response to drugs. This
relatively new fie...
3
Pharmacogenetics VS. Pharmacogenomics
Pharmacogenetics: Study of variability in drug
response determined by single genes...
4
Pharmacogenetics has been defined as the study
of variability in drug response due to heredity.
More recently, with the ...
5
The International Conference on Harmonization
(ICH) finalized a set of definitions that were
published as a guidelines i...
6
Background
The history of pharmacogenetics stretches as far
back as 510 B.C. when Pythagoras noted that
ingestion of fav...
7
 The traditional Chinese medicine with
acupuncture and herbs takes individual
variations into consideration and this sy...
8
 Since then there have been numerous landmarks
that have shaped this field of research, and have
led to the current wav...
9
 The term pharmacogenetic was first coined in
1959 by Friedrich Vogel, while the term
pharmacogenomics first began appe...
10
Genetic variation:
Primarily two types of genetic mutation events
create all forms of variations:
 Insertion or deleti...
11
Insertion or deletion of one or more nucleotide(s)
Tandem Repeat Polymorphisms
Tandem repeats occur in DNA when a patte...
12
Single Nucleotide Polymorphism
Variation within the human genome is seen about
every 500–1000 bases, although there are...
13
“A single-nucleotide polymorphism, often
abbreviated to SNP (pronounced snip;
plural snips), is a variation in a single...
14
Many drugs that are currently available are “one
size fits all,” but they don't work the same way for
everyone. It can ...
15
With the knowledge gained from the Human
Genome Project, researchers are learning how
inherited differences in genes af...
16
 A consortium between the pharmaceutical
industry and charities such as the Wellcome
Trust was formed to create a libr...
17
 Theoretically, this could be used to create
individual SNP profiles that correlate with
individual drug response. Cur...
18
A Case Study in Pharmacogenetics
 6-mercaptopurine, 6-thioguanine, azathioprine
 Used to treat lymphoblastic leukemia...
19
Pharmacogenetics: A Case Study
20
Pharmacogenetics: A Case Study
21
Pharmacogenetics: A Case Study
22
Codeine and Cytochrome P450 CYP2D6
 Codeine is a commonly used opioid
--Codeine is a prodrug
--It must be metabolized ...
23
Due to individual variation
 20-40% of patients benefit from an approved drug
 70-80% of drug candidates fail in clin...
24
Personalized Medicine
A form of medicine that uses information about a
person’s genes, proteins, and environment to
pre...
25
26
Personalized Drugs
Herceptin (breast cancer, target: Her2/neu)
Erbitux (colorectal cancer, target: EGFR)
Strattera (att...
27
The promise of personalized medicines is also
of obvious interest and importance to the
pharmaceutical industry since i...
28
Faster Clinical Trials
 Different researchers reported that therapeutic
approaches using precision medicine, which
emp...
29
This shows the importance of pairing targeted
therapy with a biomarker.
 Another sub-analysis of the precision medicin...
30
FDA Requires Genetic Tests for Certain Therapies
31
Research in the area of pharmacogenomics is
now gaining importance due to the invention of
different techniques that ca...
32
DNA Amplification Technique i.e. PCR
The polymerase chain reaction (PCR) is a technique
used in molecular biology to am...
33
Comparative Genomic Hybridization (CGH)
CGH, a special FISH technique (dual probes), is
applied for detecting all genom...
34
Multiplex Ligation-Dependent Probe
Amplification (MLPA)
MLPA is commonly applied to screen deletions
and duplications o...
35
DNA Chip Technology
Also called DNA microarray technology, is a
revolutionary new tool designed to identify
mutations i...
36
Better Treatment, Fewer Side Effects
William Phelps, the director of preclinical and
translational cancer research at t...
37
It might mean:
 testing a person’s cancer to find out if a certain
type of treatment will work on it
 looking at a pe...
38
Challenges
Although there appears to be a general
acceptance of the basic tenet of
pharmacogenomics amongst physicians ...
39
 A general feeling of lack of availability of the test
 The understanding and interpretation of
evidence-based resear...
40
Future
Computational advances in pharmacogenomics
has proven to be a blessing in research. In order
for the field to gr...
41
The field of pharmacogenomics is still in its
infancy. Its use is currently quite limited, but new
approaches are under...
42
References
 Maria Schwaederle, Melissa Zhao, J. Jack Lee, Vladimir Lazar, Brian
Leyland-Jones, Richard L. Schilsky, Jo...
43
 Sim SC, Ingelman-Sundberg M. Pharmacogenomic biomarkers: new
tools in current and future drug therapy. Trends Pharmac...
44
 Rabbani B, Khanahmad H, Bagheri R, et al. Characterization of minor
bands of STR amplification reaction of FVIII gene...
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  1. 1. 1 Overview of Pharmacogenomics Faraza Javed PhD Pharmacology
  2. 2. 2 Pharmacogenomics Pharmacogenomics is the study of how genes affect a person’s response to drugs. This relatively new field combines pharmacology (the science of drugs) and genomics (the study of genes and their functions) to develop effective, safe medications and doses that will be tailored to a person’s genetic makeup. Its name (pharmaco- + genomics) reflects its combining of pharmacology and genomics.
  3. 3. 3 Pharmacogenetics VS. Pharmacogenomics Pharmacogenetics: Study of variability in drug response determined by single genes. Pharmacogenomics: Study of variability in drug response determined by multiple genes within the genome.
  4. 4. 4 Pharmacogenetics has been defined as the study of variability in drug response due to heredity. More recently, with the fashion for adding the suffix ‘… omics’ to areas of research, the term ‘pharmacogenomics’ has been introduced. While the former term is largely used in relation to genes determining drug metabolism, the latter is a broader based term that encompasses all genes in the genome that may determine drug response. The distinction however, is arbitrary and both terms can be used interchangeably.
  5. 5. 5 The International Conference on Harmonization (ICH) finalized a set of definitions that were published as a guidelines in 2008: Pharmacogenomics: The study of variations of DNA and RNA characteristics as related to drug response. Phamacogenetics: A sub-set of pharmacogenomics, for the study of variations in DNA sequence as related to drug response.
  6. 6. 6 Background The history of pharmacogenetics stretches as far back as 510 B.C. when Pythagoras noted that ingestion of fava beans resulted in a potentially fatal reaction (Hemolytic Anemia and oxidative stress) in some, but not all, individuals. Interestingly, this identification was later validated and attributed to deficiency of 6GDP in the 1950s and called favism.
  7. 7. 7  The traditional Chinese medicine with acupuncture and herbs takes individual variations into consideration and this system is still practiced in new China.  Sysang topology, a Korean traditional medicinal system explains the individual differences in behavioral patterns, physical characteristics, and susceptibility to a certain disease based on their biophysiological trait.
  8. 8. 8  Since then there have been numerous landmarks that have shaped this field of research, and have led to the current wave of interest.  Reports of prolonged paralysis and fatal reactions linked to genetic variants in patients who lacked butyrylcholinesterase (‘pseudocholinesterase’) following administration of succinylcholine injection during anesthesia were first reported in 1956.
  9. 9. 9  The term pharmacogenetic was first coined in 1959 by Friedrich Vogel, while the term pharmacogenomics first began appearing around the 1990s and the first FDA approval of a pharmacogenetic test was in 2005 (for alleles in CYP2D6 and CYP2C19).
  10. 10. 10 Genetic variation: Primarily two types of genetic mutation events create all forms of variations:  Insertion or deletion of one or more nucleotide(s) --Tandem Repeat Polymorphisms --Insertion/Deletion Polymorphisms  Single base mutation which substitutes one nucleotide for another --Single nucleotide polymorphisms (SNPs)
  11. 11. 11 Insertion or deletion of one or more nucleotide(s) Tandem Repeat Polymorphisms Tandem repeats occur in DNA when a pattern of one or more nucleotides is repeated and the repetitions are directly adjacent to each other. Insertion/Deletion Polymorphisms An insertion/deletion polymorphism, commonly abbreviated “indel,” is a type of genetic variation in which a specific nucleotide sequence is present (insertion) or absent (deletion). While not as common as SNPs, indels are widely spread across the genome.
  12. 12. 12 Single Nucleotide Polymorphism Variation within the human genome is seen about every 500–1000 bases, although there are a number of different types of polymorphic markers, most attention recently has focused on single nucleotide polymorphisms (SNPs, pronounced snips), and the potential for using these to determine the individual drug response profile.
  13. 13. 13 “A single-nucleotide polymorphism, often abbreviated to SNP (pronounced snip; plural snips), is a variation in a single nucleotide that occurs at a specific position in the genome, where each variation is present to some appreciable degree within a population”
  14. 14. 14 Many drugs that are currently available are “one size fits all,” but they don't work the same way for everyone. It can be difficult to predict who will benefit from a medication, who will not respond at all, and who will experience negative side effects (called adverse drug reactions).
  15. 15. 15 With the knowledge gained from the Human Genome Project, researchers are learning how inherited differences in genes affect the body’s response to medications. These genetic differences will be used to predict whether a medication will be effective for a particular person and to help prevent adverse drug reactions.
  16. 16. 16  A consortium between the pharmaceutical industry and charities such as the Wellcome Trust was formed to create a library of 300000 SNPs; this project was always well ahead of the intended schedule, and has recently resulted in the publication of a SNP map comprising 1.42 million SNPs at an average density of one SNP every 1.9 kilobases.
  17. 17. 17  Theoretically, this could be used to create individual SNP profiles that correlate with individual drug response. Currently, we prescribe drugs according to the model that ‘one dose fits all’. Using SNP profiling, it may possible to tailor drug prescription and drug dosage to the individual, thereby maximizing efficacy and minimizing toxicity.
  18. 18. 18 A Case Study in Pharmacogenetics  6-mercaptopurine, 6-thioguanine, azathioprine  Used to treat lymphoblastic leukemia, autoimmune disease, inflammatory bowel disease  Interferes with nucleic acid synthesis  Therapeutic index limited by myelosuppression 6-thioguanine azathioprine6-mercaptopurine
  19. 19. 19 Pharmacogenetics: A Case Study
  20. 20. 20 Pharmacogenetics: A Case Study
  21. 21. 21 Pharmacogenetics: A Case Study
  22. 22. 22 Codeine and Cytochrome P450 CYP2D6  Codeine is a commonly used opioid --Codeine is a prodrug --It must be metabolized into morphine for activity  Cytochrome P450 allele CYP2D6 is the metabolizing enzyme in the liver  7% of Caucasians are missing one copy of the Cytochrome P450 CYP2D6 gene  Codeine does not work effectively in these individuals.
  23. 23. 23 Due to individual variation  20-40% of patients benefit from an approved drug  70-80% of drug candidates fail in clinical trials  Many approved drugs removed from the market due to adverse drug effects The use of DNA sequence information to measure and predict the reaction of individuals to drugs.  Personalized drugs  Faster clinical trials  Less drug side effects Pharmacogenetics
  24. 24. 24 Personalized Medicine A form of medicine that uses information about a person’s genes, proteins, and environment to prevent, diagnose, and treat disease. Examples of personalized medicine include using targeted therapies to treat specific types of cancer cells, such as HER2-positive breast cancer cells, or using tumor marker testing to help diagnose cancer. Also called precision medicine.
  25. 25. 25
  26. 26. 26 Personalized Drugs Herceptin (breast cancer, target: Her2/neu) Erbitux (colorectal cancer, target: EGFR) Strattera (attention-deficit/hyperactivity disorder, Metabolism: P4502D6) 6-MP (leukemia, Metabolism: TPMT) and the list is growing rapidly ...
  27. 27. 27 The promise of personalized medicines is also of obvious interest and importance to the pharmaceutical industry since it may allow streamlining of the drug development, drug testing and drug registration process, reducing the time from chemical synthesis to introduction into clinical practice, and therefore the cost of the drug development process.
  28. 28. 28 Faster Clinical Trials  Different researchers reported that therapeutic approaches using precision medicine, which emphasizes the use of individual genetics to refine cancer treatment, showed improved response and longer periods of disease remission, even in phase I trials.  In a sub-analysis of 234 arms testing targeted drugs, the authors found that using biomarkers to assign patients to treatments led to response rates of 31.1 percent compared to 5.1 percent for those that did not.
  29. 29. 29 This shows the importance of pairing targeted therapy with a biomarker.  Another sub-analysis of the precision medicine trials showed that while the use of both genomic and protein biomarkers improved outcomes, genomic biomarkers performed better. Targeting genomic alterations resulted in a 42 percent response rate compared to a 22.4 percent response if the biomarker was directed at a protein overexpression.
  30. 30. 30 FDA Requires Genetic Tests for Certain Therapies
  31. 31. 31 Research in the area of pharmacogenomics is now gaining importance due to the invention of different techniques that can be used to identify genetic variation. Recombinant DNA Techniques Joining together of DNA molecules from two different species that are inserted into a host organism to produce new genetic combinations that are of value to science, medicine, agriculture, and industry.
  32. 32. 32 DNA Amplification Technique i.e. PCR The polymerase chain reaction (PCR) is a technique used in molecular biology to amplify a single copy or a few copies of a piece of DNA across several orders of magnitude, generating thousands to millions of copies of a particular DNA sequence. Hybridization Techniques Fluorescence In Situ Hybridization (FISH) FISH is applied to provide specific localization of genes on chromosomes. This technique is used to check the cause of trisomies, microdeletion syndromes, etc.
  33. 33. 33 Comparative Genomic Hybridization (CGH) CGH, a special FISH technique (dual probes), is applied for detecting all genomic imbalances. The basics of technique is comparison of total genomic DNA of the given sample DNA (e.g. tumor DNA) with total genomic DNA of normal cells. Copy number of genetic material (gains and losses) is calculated by evaluation software.
  34. 34. 34 Multiplex Ligation-Dependent Probe Amplification (MLPA) MLPA is commonly applied to screen deletions and duplications of up to 50 different genomic DNA or RNA sequences. On the immediate horizon are even more powerful techniques, techniques that scientists expect will have a formidable impact on the future of both research and clinical genetics.
  35. 35. 35 DNA Chip Technology Also called DNA microarray technology, is a revolutionary new tool designed to identify mutations in genes or survey expression of tens of thousands of genes in one experiment. e.g. Roche Chip for Cytochrome P450 Genes: CYPC19 and CYP2D6
  36. 36. 36 Better Treatment, Fewer Side Effects William Phelps, the director of preclinical and translational cancer research at the American Cancer Society says: With targeted approach, The overall toxicity to patients should be reduced because you are more likely to use the best collection of drugs the first time around. When it comes to cancer, personalization can take several different forms currently.
  37. 37. 37 It might mean:  testing a person’s cancer to find out if a certain type of treatment will work on it  looking at a person’s genetics to decide whether he or she can handle a specific medicine, or conducting a genetic test to determine if a person has certain genetic mutations that could put them at a higher risk for developing cancer  Pretherapeutic screening does help to reduce the risk of treatment related toxicities through adaptive dosing strategies
  38. 38. 38 Challenges Although there appears to be a general acceptance of the basic tenet of pharmacogenomics amongst physicians and healthcare professionals, several challenges exist that slow the uptake, implementation, and standardization of pharmacogenomics. Some of the concerns raised by physicians include:  Limitation on how to apply the test into clinical practices and treatment
  39. 39. 39  A general feeling of lack of availability of the test  The understanding and interpretation of evidence-based research and  The cost-effectiveness of pharmacogenomics  Ethical, legal and social issues Although other factors contribute to the slow progression of pharmacogenomics (such as developing guidelines for clinical use), the above factors appear to be the most prevalent.
  40. 40. 40 Future Computational advances in pharmacogenomics has proven to be a blessing in research. In order for the field to grow, rich knowledge enterprises and business must work more closely together and adopt simulation strategies. Consequently, more importance must be placed on the role of computational biology with regards to safety and risk assessments.
  41. 41. 41 The field of pharmacogenomics is still in its infancy. Its use is currently quite limited, but new approaches are under study in clinical trials. In the future, pharmacogenomics will allow the development of tailored drugs to treat a wide range of health problems, including cardiovascular disease, Alzheimer disease, cancer, HIV/AIDS, and asthma.
  42. 42. 42 References  Maria Schwaederle, Melissa Zhao, J. Jack Lee, Vladimir Lazar, Brian Leyland-Jones, Richard L. Schilsky, John Mendelsohn, Razelle Kurzrock. Association of Biomarker-Based Treatment Strategies With Response Rates and Progression-Free Survival in Refractory Malignant Neoplasms. JAMA Oncology, 2016; DOI:10.1001/jamaoncol.2016.2129  Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31:3997–4013.  Altshuler DL, Durbin RM, Abecasis GR, et al. A map of human genome variation from population-scale sequencing. Nature. 2010;467(7319):1061– 1073.
  43. 43. 43  Sim SC, Ingelman-Sundberg M. Pharmacogenomic biomarkers: new tools in current and future drug therapy. Trends Pharmacol Sci. 2011;32(2):72–81.  Hoggatt J. Personalized medicine–trends in molecular diagnostics: exponential growth expected in the next ten years. Mol Diagn Ther. 2011;15(1):53–55.  Norton P. Peet and Philippe Bey Pharmacogenomics: challenges and opportunities. Drug Discovery Today. 2001;6:495–498.  Hoskins JM, Carey LA, McLeod HL. CYP2D6 and tamoxifen: DNA matters in breast cancer. Nat Rev Cancer. 2009;9(8):576–586.  Kiechle FL, Holland CA. Point-of-care testing and molecular diagnostics: miniaturization required. Clin Lab Med. 2009;29(3):555– 560
  44. 44. 44  Rabbani B, Khanahmad H, Bagheri R, et al. Characterization of minor bands of STR amplification reaction of FVIII gene by PCR cloning. Clin Chim Acta. 2008;39(12):114–5.  Levsky JM, Singer RH. Fluorescence in situ hybridization:Past, present and future. J Cell Sci. 2003;116(Pt14):2833–8.  Houldsworth J, Chaganti RS. Comparative genomic hybridization:An overview. Am J Pathol.1994;145(6):1253–60.  Shaffer LG, Kashork CD, Saleki R, et al. Targeted genomic microarray analysis for identification of chromosome abnormalities in 1500 consecutive clinical cases. J Pediatr. 2006;149(1):98–102.  Mullis KB, Faloona FA. Specific synthesis of DNA in vitro via a polymerasecatalyzed chain reaction. Methods Enzymol 1987;155:335–50.
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Overview of Pharmacogenomics, Genetic Variations, Biomarkers and Genetic Diagnostic Techniques

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