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PHAR 211 > Pharmacogenomics > Flashcards

Pharmacogenomics Flashcards

1
Q

What is a drug?

A

A medicine or other substance which has a physiological effect when ingested or otherwisw introduced into the body

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2
Q

What is a drug target?

A

It can be a protein, cell or organ affected by a specific drug

Can impact human host, bacteria, or viruses

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3
Q

What are the characteristics of a “good” drug?

A
  • Potent
  • Specific
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4
Q

What is the reason for drug failures in the drug development process?

A

Flawed biological hypothesis (wrong target chosen)
- often due to a lack of understanding of the fundamental molecular mechanisms

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5
Q

What are some challenges in drug development?

A
  • Identify all the protein/genes that can be a potential target
  • Identify all compunds that can be used as drugs
  • Confirmation that a compund inhibits the intended target
  • Identification of undesirable secondary effects
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6
Q

How are potential drug targets identified by drug manufacturers/researchers?

A
  1. Data-mining (using existing literature to find associations between genes and disease)
  2. Genetic/Genomic approaches (compare protein and transcriptome arrays)
  3. in vitro approaches
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7
Q

How are drug targets validated?

A
  1. Does target knock-out have the desired effects?
  2. Where in the body is the gene expressed, does it vary with age or sex
  3. Are there alternate pathways available (need to target chokepoints)
  4. Can we execute a drug-discovery program
    - Is the target druggable (good access and afinity due to pocket morphology)
    - Is selectivity necessary/acheivable
    - Is there a suitable animal model system
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8
Q

What are chokepoints in drug targets?

A

Drugs should target the step that has no alternate pathways to the substance you want to modulate

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9
Q

What is the difference between forward and reverse chemical genetics (chemogenomic screens)?

A

Forward chemical genetics: chemical identified first and given to target, see which chemical worked, then check how it is causing effect

Reverse chemical genetics: Identfiy target first, then visit compound library to find chemical that will bind to target, then determine efficacy

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10
Q

What is a druggable genome?

A

It is the number of genes that code for proteins that are druggable

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11
Q

What is the basic principles of drug target networks?

A
  1. One drug may target multipe proteins
  2. One protein may be binded by multiple drugs
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12
Q

What is the definition of druggability?

A

Ability fo a protein to be modulated by a drug-like small molecule, biologics, etc.

Drug should have complementary structure to the target site

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13
Q

What are the methods of assessing druggability?

A
  1. Sequence-based
    - Predicted druggable based on sequence features (DNA, protein sequence)
  2. Structure-based
    - Protein structure contains drug-like pockets
    - Protein binds to endogenous drug-like ligands
  3. Ligand-based
    - High affinity drug-like compunds available
    - Compounds in clinical trials for the protein
    - Protein is an established small molecule drug target
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14
Q

What is the current state of antibacterial drug development?

A
  1. Antibiotic discovery has slowed down
    - reduced economic viability (small volume sold vs chronic drugs)
    - increased liability claims for adverse events (they show up before company has had opportunity to make money from drug)
  2. Antibiotic resistance is increasing (so new agents may also be ineffective)
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15
Q

What is the PASTEUR Act in the United States?

A

The governement has agreed to compensate pharma companies to develop new antibiotics.

This incentive is given because the value of new antibiotics to society is much greater

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16
Q

How are drug targets for antibacterial drugs chosen?

A
  1. Compare sequence of all strains and find what sections are conserved between all strains (they are probably essential for normal functioning)
  2. Ensure selected bacterial conserved sequence does not show up in the human genome (prevents the antibacterial from targeting the human)
  3. Mutagenic studies, knock out conserved proteins in bacteria and study impact
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17
Q

What are some commonly chosen targets for antibacterial drugs?

A

Targets should target organism without affecting the host. This is done by attacking processes that are critical to microbial well-being, but not mammallian systems

  • Bacterial cell wall
  • Inhibition of an enzyme unique to bacteria
  • Disruption of bacterial protein synthesis
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18
Q

What is the benefit of using genomics to pharmaceutical development?

A
  • Optimize pre-clinical therapeutic target
  • Reduce R&D costs
  • Maximize success of clinical trials
  • Expedite FDA approvals
  • Decrease time to market
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19
Q

What is the K-value paradox?

A

Complexity does not correlate with chromosome number

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20
Q

What is the C-value paradox?

A

Complexity does not correlate with genome size

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21
Q

What is the N-value paradox?

A

Complexity does not correlate with gene number

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22
Q

Why are mice the model of choice for pre-clinical drug discovery?

A
  • Less ethically polarizing
  • The human and mouse genome are similar and contain many of the same genes
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23
Q

What is the difference between pharmacogenetics and pharmacogenomics?

A

Pharmacogenetics: study of variability in drug response determined by a single gene

Pharmacogenomics: study of variability in drug response determined by multiple genes within the genome

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24
Q

What are the three categories of patients in terms of their response to therapy?

A
  1. Responders
  2. Non-responders
  3. Toxic responders
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25
Q

Why do some patients respond to therapy differently vs other patients?

A
  • SNPs
  • Ethnicity
  • Age
  • Disease
  • DIs

See slide 53

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26
Q

What is the frequency of SNPs in an individuals genome?

A

SNPs occur with an average frequency of 1 per 300-1000

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27
Q

How frequent in the population does a single nucleotide mutation need to occur for it to be considered a SNP?

A

At least 1% of the population should have the SNP

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28
Q

What is a potential impact of a SNP that codes for a protein?

A

A SNP can potentially change the codon as read by RNA transcriptase

This eventually results in a protein with one amino acid that is different (can result in no effect, improved function, or reduced function due to changes in structure and function)

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29
Q

How does warfarin reduce blood clotting?

A

Inhibits the reduction of Vit K, and results in reduced clotting factor production

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30
Q

What are the three genes that are associated with Warfarin use?

A
  1. CYP2C9 gene (codes for an enzyme that breaks Warfarin)
    - Variants of this gene need lower warfarin doses
  2. CYP4F2 gene (codes for an enzyme that reduce ability to metabolize warfarin)
    - Variants of this gene need higher warfarin doses
  3. VKORC1 gene (codes for an enzyme that helps reduce Vitamin K)
    - Variants of this gene need lower warfarin dose
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31
Q

What is the CFTR protein?

A

The CFTR protein functions as a chloride channel

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32
Q

What is the consequence of a CTFR protein mutation?

A

This mutation can result in the accumulation of chloride in lung membrane cells, causing water to enter and trigger the production of a thick, sticky mucous

This mucous can pose increased infection risk

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33
Q

What are the characteristics of Class I CFTR mutation?

A

NO CFTR protein (no chloride transport)

Therefore overproduction of mucous

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34
Q

What are the characteristics of Class II CFTR mutation?

A

Little to no CFTR protein (impaired chloride transport)

Overproduction of mucous

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35
Q

What are the characteristics of a Class III CFTR mutation?

A

Normal amount of CFTR protein, but no cloride transport (closed protein)

Overproduction of mucous

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36
Q

What causes the lack of CFTR protein in those who have a mutation on that gene?

A

In patients with CFTR mutations, they may have a SNP that causes a stop codon halfway through transcribing CFTR. This results in a smaller non-functional pre-CFTR protein

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37
Q

How does Ataluren improve symptoms associated with a CFTR mutation in Cystic Fibrosis?

A

Ataluren causes transcription to perform read-through transcription (skip the stop codon created by the mutation) and results in a fully formed CFTR protein

This treatment can result in creased number of CFTR proteins, increasing K+ transport out of the cell, and less mucous

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38
Q

What drug is used for therapy in Class III CFTR mutation Cystic Fibrosis?

A

Kalydeco can open up the endogenous CFTR protein and allow efflux of K+, which causes reduction in mucous production

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39
Q

What is the utility of Trikafta in treatment of Cystic Fibrosis?

A

Trikafta is a triple comination therapy and targets both mechanisms by which a CFTR mutation can cause Cystic Fibrosis. Therefore, there is no need to gene sequence patient to determine what mutation they have.

Increase production of CFTR:
- Elexacaftor
- Tezacaftor

CFTR proteins do not open correctly:
- Ivacaftor (Kalydeco)

40
Q

What are anti-sense oligonucleotides (ASO)?

A

They are single stranded nucleic acids that hybridize with complementary mRNA in a sequence-specific manner

41
Q

What are the consequences of anti-sense oligonucleotides in the nucleus?

A

Due to hypbridization with complementary mRNA strand, the following is possible:
- Inhibition of RNA splicing (if ASO is on exon-intron boundary)
- Inhibition of 5’ cap formation (if ASO is located at 5’ end)
- Activation of RNase (breakdown of mRNA strand)

42
Q

What are the consequences of anti-sense oligonucleotides in the cytosol?

A

Due to hybridization with the complementary mRNA strand, the following is possible:
- Activation of RNase H
- Steric hinderance of ribosomal subunit binding

43
Q

What is the suffix for ASO (anti-sense oligonucleotide) drugs?

A

End in -rsen

44
Q

What gene contains the mutation that causes Duchenne muscular dystrophy?

A

Dystrophin (it is the largest gene and contains 79 exons)

Mutations in DMD can occur throughout the length of the gene (prevalently characterized by large deletions and single point mutations)

45
Q

Are female patients at greater risk of Duchenne muscular dystrophy?

A

No, males are at disproportionately higher risk due to dystrophin being found on the X chromosome (men only have one copy, while women have two copies)

Women with carrier status for DMD have muscle weakness to some extent

46
Q

What is the use of Eteplirsen in treatment of Duchenne muscular dystrophy?

A

It is an anti-sense oligonucleotide that causes exon skipping in the pre-mRNA. This results in the bypass of an exon that contains a premature stop codon. The result is shorter, but functional dystrophin protein

47
Q

What is spinal muscular atrophy (SMA)?

A

It is a neurodegenerative disease primarily characterized by a loss of spinal motor neurons (SMN).

48
Q

What is the etiology of spinal muscular atrophy?

A

Two identical genes code for SMN1 and SMN2, most of the function protein is from SMN1 gene

A mutation on the SMN1 gene can impact production of the SMN protein

49
Q

How does nusinersen work in the treatment of spinal muscular atrophy?

A

It is a modified anti-sense oligonucleotide drug that targets the splicing of SMN2 in away that results in a stable, functional protein allowing it to substutue for mutated SMN1 gene

50
Q

How do molecular glue drugs work?

A

They have two different binding sites for two different proteins. The pharmalogical benefits of this drug brings two proteins that would otherwise not interact with each other.

ex. Ubiquitin targeting of a protein

51
Q

What are the major changes in cancer cells that make them uncontrollable?

A
  1. Sustained proliferative signalling (maintained growth)
  2. Evading growth suppressors
  3. Activating invasion and metastasis
  4. Enabling replicative immortality
  5. Inducing angiogenesis
  6. Resisting cell death
52
Q

What is the etiology of chronic myeloid leukemia?

A

A shortened chromosome 22 resulting from the translocation between chromosome 9 and 22

Produced BCR-ABL fusion oncogene and encodes for a overproducing activated kinase

This kinase promotes the phosphorylation of a substrate which causes chronic myleloid leukemia

53
Q

What is the mechanism of action for imatinib?

A

Imatinib (Gleevec) was one of the first tyrosine kinase inhibitors (used for treatment of chronic myeloid leukemia)

Imatinib binds to the ATP binding site on BCR-ABL protein, preventing phosphorylation of substrate (preventing leukemia)

54
Q

What are some types of BCR-ABL dependent resistance to Imatinib?

A
  • BCR-ABL duplication (increased production of BCR-ABL, more protein for the same dose)
  • BCR-ABL mutations (imatinib no longer binds to the ATP binding site of BCR-ABL)
55
Q

What are some types of BCR-ABL independent resistance to Imatinib?

A
  • Changes in influx and efflux of Imatinib
  • Alternate signalling pathway activation (a different mechanism not inhibited by Imatinib is causing cell proliferation)
56
Q

What happens to the NTRK gene in TRK fusion cancers?

A

The NTRK gene fuses with an unrelated gene that results in constitutively activated chimeric TRK fusion proteins that result in cell proliferation and tumour growth leading to TRK fusion cancer

57
Q

What is VITRAKVI (Larotrectinib) indicated for?

A

VITRAKVI is indicated for treatment of adult and pediatric patients with solid tumurs that have a NTRK gene fusion

It is a NTRK inhibitor

58
Q

What is a special characteristic of Entrectenib (Rozlytrek)?

A

It is the only NTRK inhibitor that is clinically proven to be effective against primary and metastatic brain diseases

59
Q

Why is human EGFR an attractive target for anti-cancer therapy?

A

EGFR is dysregulated in many solid tumours

60
Q

What are the main mechanisms by which antibodies help treat cancer?

A
  1. Binding of the antibody can elicit an immune response (causing the body to kill the cancer cells, NK cells)
  2. Drugs (toxins, radio-isotopes, etc.) can be attached to the antibody and delivered specifically to the cancer cell, leading to cell death
61
Q

What is the function of HER2?

A

HER2 is a cell transmembrane surface bound receptor tyrosine kinase that is normally involved in signal transduction pathways for cell growth and differentiation (occurs when HER2 dimerizes with other HER2 proteins)

62
Q

What is the difference in HER2 expression in healthy and cancer cells?

A

Healthy cells: 20,000 receptors

Primary breast cancers: more than 2 million (100x more receptors)

This massive difference is why uncontrolled proliferation is in overdrive for HER2 breast cancer cells

63
Q

What is herceptin (Trastuzumab)?

A

It is a monoclonal antibody that works on extracellular and intracellular domain of HER2 receptors

It flags HER2 positive cells for immune system mediated death by NK cells

64
Q

What is pertuzumab?

A

It is a monoclonal antibody for HER2 positive breast cancer

It inhibits HER2 protein from dimerizing (active form)

65
Q

What does dimerized HER2 protein do to cause cell proliferation?

A

It amplifies signal transduction and promotes the formation of spindles (required for cell division)

66
Q

How do EGFR inhibitors help treat cancer?

A

They bind to extracellular receptors for EGF (epidermal growth hormone) and inhibit the signal transduction patway that results in cellular proliferation

67
Q

Why are colon cancers with KRAS mutations resistant to EGFR inhibitor therapy?

A

KRAS is uneffected by EGF inhibiton (it is an alternative pathway to get to cell proliferation)

40-45% of colon cancer patients have KRAS mutation, limiting the usefulness of EGFR inhibitors

68
Q

What is the target for Avastin (Bevacizumab)?

A

It is an antibody for VEGF (main regulator for angiogenesis)

Cancer cells produce VEGF to improve vascularization of tumour, inhibition of VEGF can limit the blood supply to tumour. This will slow down proliferation

69
Q

What are MMPs

A

They help dissolve extracellular material to improve ease of blood vessel extension as stimulated by VEGF

70
Q

What is the mechanism of action of BiTE (Bispecific T-cell engagers) antibodies?

A

BiTEs bring target cells or tissue (one antigen binding site) in contract with cytotoxicity triggering molecules like T-cells (second antigen binding site)

This results in the formation of cytolytic synapse between the T-cell and cancer cell

71
Q

What CYP450 enzyme metabolizes Codeine?

A

CYP3A4 (major pathway): forms inactive metabolites

CYP2D6 (minor pathway): metabolism forms active drug

72
Q

What are some drugs when dosed concomittently that can cause codeine toxicity?

A

Clarithromycin can inhibit the major metabolism pathway for codeine (CYP3A4), leaving more drug to be metabolized by the minor pathway, but this results in the active form of codeine (results in toxicity)

73
Q

What CYP450 enzyme metabolizes antiplatelet drugs?

A

CYP3A4 is the major drug metabolizing enzymes for Ticagrelor, Clopidogrel, and Prasugrel

74
Q

What are some drugs that can inhibit metabolism of antiplatelets?

A

Strong CYP3A4 inhibitors:
- Ketoconazole
- Clarithromycin
- Nefazadone
- Ritonavir
- Atazanavir

Avoid using these drugs concomittently with antiplatelets

75
Q

What are the ten hallmarks of cancer?

A
  1. Resisting cell death
  2. Sustaining proliferative signalling
  3. Evading growth suppressors
  4. Activating invasion and metastasis
  5. Enabling replicative immortality
  6. Inducing angiogenesis
  7. Deregulating cellular energetics
  8. Avoiding immune destruction
  9. Genome instability and mutation
  10. Tumour-promoting inflammation
76
Q

What are some factors that can impact successful targeting of drugs to tumour cells?

A
  1. Tumour heterogeneity
  2. Antigen shedding
  3. Antigen modulation
  4. Evading immune response
77
Q

What is tumour heterogenicity?

A

The surface composition of tumour cells in a tumour is not uniform, neither in stage of development or cell type

This introduces variation in target sites (no one targeted drug will bind to all of the tumour cells)

78
Q

What challenges does tumour heterogeneity impact the ability to capture therapeutically relevant information about the tumour?

A
  • Tumour sampling is invasive and sometimes not feasible or adequate because of practical, clinical, and logistical factors
  • May not be contemporaneous to the clinically significant disease process (things may have changed)
  • Sample could be from an uninformative part of a tumour deposit
  • Some detection techniques may not be sufficiently sensitive to detect low frequency
79
Q

What is the consequence of antigen shedding on targeted therapies?

A

The antigens are released from the surface of the tumour. These free antigens will interact with the drug antibodies and neutralize the targeting potential of the conjugates (drug does not come close to actual tumour)

80
Q

What is antigen modulation?

A

The originally exposed surface antigen is taken into the cell and is not replenished

81
Q

What are some challenges with developing cancer vaccines?

A
  1. Cancer cells suppress the immune system (oppose MOA of cancer vaccines)
  2. Cancer cells start from a person’s own cells (cancer-specific antigens can be hard to find
  3. Larger and more advanced tumours are hard to get rid of using only a vaccine
  4. People who are sick have weaker immune systems (limited ability to attack cancer despite induction)
  5. Each individual’s tumour is in some sense unique and have their own distinguishing antigens (but abnormal signatures can help distinguish them)
82
Q

Do preventative cancer vaccines exist?

A

Not really, but some vaccines target viral infections that are associated with cancer (indirect cancer prevention)

ex. HPV (cervical & head and neck cancer) and HBV (liver cancer) vaccines

83
Q

What are some qualities of cancer vaccines in preventing remission?

A
  • Keep the cancer from coming back
  • Destroy any cancer cells still in the body after treatments end
  • Stop a tumour from growing or spreading
84
Q

How do therapeutic cancer vaccines work?

A

They are a type of immunotherapy. They work to boost the body’s immune system to fight cancer

85
Q

What are the types of therapeutic cancer vaccines?

A
  • Bacillus Calmette- Guerin
  • Sipuleucel-T (composed of the patient’s antigen presenting cells and it used for prostate cancer)
  • CAR-T cell therapy
  • Immune checkpoint inhibitors
  • Personalized Neoantigen Vaccines
86
Q

What are some characteristics of Bacillus Calmette-Guerin (BCG) treatment of bladder cancer?

A

Uses weakened bacteria to stimulate the immune system against early-stage bladder cancer

Given after surgical resection of bladder tumour (ensures full removal of visible cancer)

87
Q

Review slide 131 for a review of basic immunology

A
88
Q

What is Sipuleucel-T used to help treat?

A

It is a cancer vaccine for prostate cancer (antigen presenting cells from patient are matched to antigens associated with prostate cancer, and are reintroduced into the patient)

89
Q

What is the function of cytotoxic T cells?

A

Upon activation by an antigen presenting cell, cytotoxic T cells bind and kill infected cells and cancer cells

90
Q

How does CAR-T cell therapy work?

A
  1. T-cells are removed from patient
  2. Insert chimeric antigen receptor (CAR) gene into patient’s T-cells (only binds to cancer cells)
  3. Grow millions of CAR T cells
  4. Infuse CAR T cells into patient
  5. CAR T cells bind to cancer cells and kill them
91
Q

What is a side effect of CAR T-cell therapy?

A

Cytokine release syndrome (CRS) can cause high fevers and drops in blood pressure

Can be managed by supportive therapies including steroids or IL-6 blockers

92
Q

What are immune checkpoint inhibitors?

A

These drugs basically take the “brakes” off the immune system, which helps it recognize and attack cancer cells

(block PD-1 receptors on T-cells)

93
Q

What is a surface molecule found on cancer and fetal cells that allows them to evade immune attack?

A

PD-L1/PD-L2

94
Q

How do PD-L1 (programmed cell death ligand) molecules on cancer cells allow them to evade immune response?

A
  • The PD-1 receptor is on T-cells (supresses T-cell activity if activated)
  • Reduce immune response after disease elimination
  • Prevent damage from inflammatory response
95
Q

What is the consequence of PD-1 activation?

A
  • T-cell apoptosis
  • Downregulation of cytokine production
  • Suppression of anti-tumour response
96
Q

What are some examples of immune checkpoint inhibitors (receptor targeted)?

A
  • Nivolumab (PD-1)
  • Pembrolizumab (PD-1)
  • Ipilimumab (CTLA4)
97
Q
A

PHAR 211 (18 decks)

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