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Personalised Medicine > Cancer And Drugs > Flashcards

Cancer And Drugs Flashcards

1
Q

What is cancer and what are the most common cancers

A

Cancer is a temporary she does it with abnormal cells divide without control and can invite nearby tissue including the blood and lymph system which is called metastasis

The most common cancers are in the breast, prostate, lung and bowel

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2
Q

What are the four stages of cancer progression

A

Initiation - loss of tumour suppressor genes or interaction of carcinogens with DNA

Promotion - activation of an oncogene (formation of a small benign growth/polyp)

Progression - loss of another TSG (larger benign growth/adenine)

Malignant conversation - loss of another TSG plus another mutation = carcinoma

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3
Q

What health alterations occur as a result of cancer

A

Genomic - mutation, loss/gain, promoter methylation

Protein - mutant form, overexpression

Pathways - activated cell survival, loss of apoptotic cells

Biology - limitless replication, angiogenesis, tissue invasion

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4
Q

What are the factors to consider when treating cancer

A

Clinical implementation of NGS
Conduction of bio marker clinical trials
Finding of predictive markers for immunotherapy and precision immunooncology
Tumour heterogeneity and resistance

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5
Q

Why should we consider clinical implementation of NGS in cancer

A

There are not many predicted genomic abnormalities to be tested for across different cancers

When they are found they are very diverse and harder to test for this require highly advanced techniques such as NGS

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6
Q

Why should we consider conducting bio marker driven clinical trials for cancer drugs

A

These investigate early signals and require multicentre investigation

Allocate the right patient to the right trial to the right therapy

However tumour molecular heterogeneity can get in the way as a single biopsy isn’t representative of the whole tumour

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7
Q

Why should you consider tumour heterogeneity and resistance when treating cancer

A

The capacity to study heterogeneity and study mutations that may confirm resistant to treatment can help decide the most appropriate treatment for that patient

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8
Q

Why should you consider predictive markers for immunotherapy and precision immunooncology when treating cancer

A

So you know where you have a look for other ways to exploit the immune system to tackle cancer such as the use of CAR-T cells with CRISPR-Cas9

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9
Q

What was the traditional view of cancer progression and development including the primary characteristics, treatment and agents

A

Primary characteristic – uncontrolled cell division

Primary treatments

Chemotherapy – inhibit DNA replication and disrupt microtubule function
(Affects other rapidly dividing cells e.g. hair, skin, epithelial cells = large side effects)

Agents
Alkylating agents – Damage mtDNA and nuclear DNA via adding alkane groups leading to breaks in DNA and may add point mutations
Antimetabolite, topoisomerase inhibitors, anthracyclines

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10
Q

What is topoisomerase

A

Topoisomerase also plays an important maintenance role during DNA replication. This enzyme prevents the DNA double helix ahead of the replication fork from getting too tightly wound as the DNA is opened up.

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11
Q

What is the modern view of cancer including its primary characteristics and treatment

A

Primary characteristics – specific mutations drive cell division (clonal heterogeneity)

Treatment = targeted therapies
Drugs and other substances that interfere with specific molecular targets involved in the growth, progression and spread of cancer

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12
Q

Compare chemotherapy and targeted therapies

A

Chemotherapy
Kills all rapidly dividing cells - cancerous and normal
Cytotoxic
Mainly I.v. and some oral agent

Targeted therapies
Designed to interact with their specific molecular target associated with cancer
Cytostatic
May are oral agents

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13
Q

What is the breast cancer traditional diagnosis TNM system

A

TNM System

T = tumour size, 1-4
N = lymph node status, 0-3
M = metastasis, 0-1
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14
Q

What are the breast cancer traditional histopathological types

A

Classified by site, invasion, histology and differentiation

In situ carcinoma - can be ductal or lobular, good prognosis

Invasive/infiltrating carcinoma - tubular, ductal lobular, invasive ductal/lobular, infiltrating ductal, mucinous (colloid), medullary

Poor differentiation = more aggressive

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15
Q

What is the breast cancer traditional diagnosis grade system

A

Grade 1 - low grade = well differentiated
Normal epithelial morphology, less aggressive, better prognosis and survival

Grade 2 - intermediate = moderately differentiated

Grade 3 - high grade = poorly differentiated
Most have mesenchymal phenotypes

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16
Q

What is the breast cancer traditional diagnosis within immunohistochemistry

A

This is an investigation of the receptor status via immunohistochemistry
Oestrogen, progesterone and HER2 receptors

10-20% or triple negative across the three receptors – bad prognosis

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17
Q

Describe the modern breast cancer diagnosis

A

This is based on gene expression microarrays

It is classified into six subjects based on differences in the gene expression

Basal-like, ERBB2 receptor +ve , normal breast-like cancer, luminal subtype A, B and C

This results in a specific treatment and less use of chemotherapy

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18
Q

Describe the treatment decisions within lung cancer

A

85% are known for the lung cancer which are treated with platinum based chemotherapy

Traditionally decisions were based on histological classification such a large cell and small cell (squamous or adenocarcinoma)

Now classification is based on genes such as the EGFR mutation

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19
Q

Describe the aims and priorities of the 100K and genome

A

Parties – rare disease, cancer (germline and somatic), infectious disease

Aim – to improve treatment and outcomes through personalised medicines including finding new potentials for therapies

Comparing DNA sequences in case and controls using whole genome sequencing

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20
Q

What is the primary characteristic of cancer

A

Specific locations drive cell division (clonal heterogeneity) with selected pressures

Antigenicity, growth rate, hormones, cytotoxic drugs, capacity for invasion and metastasis

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21
Q

What are driver mutations

A

Driver mutations are required for carcinogenesis and convert growth and survival advantage

This can lead to secondary mutation growth – passenger mutation as well as more driver mutations

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22
Q

What are targeted cancer therapies

A

Drugs or other substances that block the growth and spread of cancer by interfering with specific molecules (“molecular targets”) involved in the growth, progression, and spread of cancer

Increase specificity and decrease toxicity

Targeted therapies include surgery, chemotherapy, radiation therapy and hormone therapy

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23
Q

What categories of targeted therapies are there

A

Targeted therapies include surgery, chemotherapy, radiation therapy and hormone therapy

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24
Q

What are the 5 different modes of action of targeted cancer therapies

A 
Signal transduction inhibitors
Gene expression modulators
Apoptosis inducers
Angiogenesis inhibitors
Immunotherapies
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25
Q

How do signal transduction inhibitors work

A

It blocks the activity of molecules that participate in signal transduction

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26
Q

How do gene expression modulators work

A

It modifies the function of proteins that play a role in controlling gene expression

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27
Q

How do apoptosis inducers work

A

It causes cancer cells to undergo apoptosis

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28
Q

How do angiogenesis inhibitors work

A

They block the growth of new blood vessels to tumours

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29
Q

How do immunotherapies work

A

They trigger the immune system to destroy cancer cells

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30
Q

What are the molecular classifications of targeted therapies

A

Small molecule inhibitors

Monoclonal antibodies

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31
Q

Describe small molecule inhibitors

A

These interfere with the extracellular signalling of tyrosine kinases

Found in EGFR and BGF receptors as transmembrane receptors but others can be intracellular

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32
Q

What are tyrosine kinases and what does their activation lead to

A

Tyrosine kinase = enzymes that transfer phosphate from ATP to tyrosine AA residues

These lead to proliferation, growth, migration and angiogenesis in normal and malignant tissues

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33
Q

How are small molecule inhibitors administered and manufactured

A

Usually administered orally

Chemically manufactured - cheaper than monoclonal antibody production

34
Q

What are the benefits and drawbacks of small molecule inhibitors

A

Benefits
Cheaper than monoclonal antibody production
Oral administration

Drawbacks
Less specific targeting than mAbs
Half-lives of only hours - daily dosing is required
Metabolised by cytochrome p450 - may interfere with other medications

35
Q

Describe how monoclonal antibodies work

A

Recruit host immune functions to attack target cells - NK killer cells, complement cascade

Bind to ligands or receptors to interrupt cell functions for proliferation

Hold a lethal payload e.g. radioisotopes or toxins to target cells (conjugated mABs)

36
Q

What are the benefits and drawbacks of monoclonal antibodies

A

Benefits
The FAB of the mABs recognises antigens and enables specificity
Not subject to drug interactions
Half-lives of days/weeks thus administered every 1-4 weeks

Drawbacks
Administered intravenously
More expensive

37
Q

What are 2 examples of small molecule inhibitors and their uses/targets

A

Imantinib - inhibits tyrosine kinase enzymes, used for chronic myeloid leukaemia against BCR-ABL

Erlotinib - targets EGFR, non-small cell lung cancer and pancreatic cancers

38
Q

What is the BCR-ABL oncogene product and what are its effects

A 
BCR = ubiquitous promoter
ABL = tyrosine kinase, which becomes unregulated, which requires ATP

Unregulated BCR-ABL
Proliferation of progenitor cells in the absence of growth factors
Decreased apoptosis
Decreased adhesion to bone marrow stroma

39
Q

What is imatinib’s mechanism of action

A

Imatinib occupies the TK active site, leading to decreased protein activity
Cross effects to some other TK enzymes

40
Q

What is erlotinib’s mechanism of action

A

Reversibly binds EFGR, inhibiting binding of ATP preventing phosphorylation

Resistance can occur with mutation of T790M, found in many patients (50-60%)

There are 3rd gen EGFR inhibitors that irreversibly covalently bond T790M mutants (Osimertinib)

41
Q

What is non-small cell lung cancer

A

ANS

15-20% of NSCLC due to EGFR mutations

HER2 overexpressed in some non-small cell lung or breast cancers
Associated with advanced disease, metastasis and poor survival
Thus it can be a key target

42
Q

What is EGFR (HER1)

A

HER1/EGFR gene encodes for part of the human epidermal growth factor receptor, a TK receptor

Important in regulating proliferation, differentiation, angiogenesis

Mutations in this gene cause protein/receptor autophosphorylation (on position)

43
Q

What receptors are involved in the HER group

A

• HER group contains of 4 transmembrane receptors

HER1/EGFR, HER2, HER3 and HER4

They can heterodimerise for signalling diversity

HER1 and 2 are the most commonly involved

44
Q

Give some examples of monoclonal antibody therapies

A

Ipilimumab - CTLA-4 Nivolumab and pembrolizumab - anti-PD1

Trastuzumab (Herceptin) and Pertuzumab - HER2+ breast cancer

45
Q

What conditions does Ipilimumab, Nivolumab and Pembrolizumab treat

A

Melanoma, hepatocellular cancer, MSI-H colorectal cancer, urothelial carcinoma, head and neck cancer, Classical Hodgkin Lymphoma, Renal Cell Carcinoma and NSCLC

46
Q

What are the roles of CTLA-4 and PD-1

A

CTLA-4 and PD-1 are surface receptors which act as immune checkpoint negative regulators to function as brakes of T-cells

Tumour cells can form ligands against these to pretend they are normal cells

Antibodies against CTLA-4 and PD-1 inhibit the brake function allowing activated T-cells to attack cancer cells

47
Q

What is the role of HER2

A

Receptor dimerization is required for HER2 function - homo or heterodimers

HER2 has intracellular TK activity
Heterodimers can trigger a cascade that triggers pathways that can be involved in activation of cell survival, proliferation and motility

Promotes intracellular P27 mislocalisation/degradation
P27 regulates the cell cycle and leads to cell repression

48
Q

What are some examples of other targeted cancer therapies

A

PARP inhibitors - BRCA1/2 e.g. Olaparib in ovarian cancer

Hormone therapies - tamoxifen (ER+ breast cancer), abiraterone and enzalutamide (metastatic castration resistant prostate cancers)

CAR-T cell therapy

49
Q

Describe how PARP inhibitors work

A

They cause synthetic lethality in cancer cells - PARP is blocked which leads BRCA mutated cells to die

Role or BRCA1/2
DNA repair proteins involved in the ds strand break repair mechanisms
These ds breaks can occur due to ionising radiation

PARP - this is involved in base excision repair - single strand breaks

Single strand breaks accumulate, which leads to accumulated ds breaks, which normal BRCA can repair, but mutated cells do not

Therefore normal cells can repair (also they don’t replicate as much) but cancer cells will die

50
Q

Describe how tamoxifen works in breast cancer

A

Used for ER+ breast cancer

About 80% of all breast cancers are ER-positive

Tamoxifen enters cancer cells and binds to oestrogens receptors, competing with oestrogen

These cancer cells needs oestrogen to grow

It can lower the risk of breast cancer in women with family history of disease, or with BRCA mutations and to prevent recurrence

51
Q

Describe how abiraterone and enzalutamide works for mCRPC

A

These target androgen receptor access preventing it from acting as TF in metastatic castration resistant prostate cancer

Androgens promote growth, survival and proliferation

Abiraterone = reversibly inhibits the first enzyme involved in androgen synthesis

Enzalutamide - blocks androgens from binding the cytoplasmic androgen receptor - inhibiting translocation of androgens, and their binding

52
Q

When is enzalutamide and abiraterone prescribed

A

Enzalutamide is prescribed in combination with Docetaxel chemotherapy with abiraterone prescribe it this doesn’t work

53
Q

Describe CAR-T cell therapy

A

T-cells get changed in the lab by adding CAR receptor (chimeric antigen receptor)

Each CAR is designed for a specific antigen, made from the patient’s own T-cells and the gene inserted using CRISPR-Cas9

Before infusion, weak chemotherapy is given to reduce other immune cells so the CAR-T cells work

These replicate inside the patient and proliferate to kill more cancer cells

54
Q

Sources of variation in drug response

A

Diagnosis - if the diagnosis is not correct, the response will be different

Compliance

Pharmacokinetics - absorption, distribution, metabolism and excretion (ADME)

Interactions with other drugs - e.g. one drug may induce the metabolism of the other

Pharmacodynamics - variation in what the drug does to the body

55
Q

What is pharmacogenomics

A

The study of how genetic differences between patients account for differences in their responses to a drug

Of all the variation in drug response, how much of it is down to your genes?

56
Q

What responses to drugs can genetic differences influence

A

Proteins produced by genes can influence

How the body processes the drug: Pharmacokinetics

How the drug affects the body: Pharmacodynamics e.g. via variation in receptors

Other things too, e.g
Comorbidity
Concomitant medications
Compliance

57
Q

What are the benefits of pharmacogenetics

A

Best outcome - benefit, and no toxicity

58
Q

What current factors can stratify patients into groups for a given disease

A

Benefit - E.g. histology of a cancer, eosinophils for asthma, BP for PE thrombolysis

Toxic - E.g. long QT, liver or renal failure, frequent falls (warfarin)

59
Q

How can you apply pharmacogenetic knowledge

A

Understand how the gene variant effects a drug response and whether you should

Adjust dosage
Choose a different drug

60
Q

Pharmacokinetics V pharmacodynamics

A

Pharmacokinetics = absorption, distribution, metabolism and excretion

Pharmacodynamics - receptors, ion channels, enzymes, immune system

61
Q

Describe hypersensitivity reaction (HSR) to Abacavir

A

Abacavir is an antiretroviral used for HIV

Hypersensitivity - fever and rash, constitutional, GI and respiratory symptoms

HLA-B*5701 allele more common among patients with HSR to abacavir Vs those who do not

62
Q

Describe what azathioprine does

A

It is a pro-drug for 6MP - blocks purine metabolism, kills WBCs

63
Q

State azathioprine’s benefits and its drawbacks

A

Upside: Treats leukaemia and inflammatory disease (IBD)

Downside: Kills you from sepsis as too much = not enough WBC’s

64
Q

How can you tailor azathioprine dosage to genetics

A

6-MP is metabolised by TPMT
Someone with low activity of TPMT therefore would have too much 6-MP

Found trimodal variation of enzyme activity - variation dependent upon genetics

Homozygous dominant, homozygous recessive and in the middle = heterozygous

Dose adjustments required based on genetics

65
Q

What are the phases of pharmacological metabolism

A

Phase I - redox hydrolysis, CYP450

Phase II - conjugation with sulphation or glucuronidation to make it more readily excreted

Phase III - export with P-glycoprotein

Excretion- CYP2D6 (part of the CYP450 subfamily)

66
Q

What does clopidogrel do

A

Prevents platelet activation - hence reduces arterial thrombosis

Important drug for MI - 20% reduction in events

67
Q

How is clopidogrel transported

A

n the intestine the transporters takes it into the bloodstream to then go to the liver
○ This is a prodrug so it must be metabolised to activated this binds the P2Y12 receptor on platelets

CYP2C19 helps metabolise the prodrug

68
Q

What are the allelic variants for CYP2C19 - and what risks may an individual face with a given variant

A

CYP2C19 have many different allelic variants; poor, intermediate, normal, rapid and ultra-metabolisers

The allelic frequency differs across ethnicities

Poor/intermediate metabolism = the drug might not work - higher risk of in-stent thrombosis as the benefit of clopidogrel is not there

69
Q

What is CYP2D6

A

An enzyme, part of the CYP450 subfamily, that helps excretion and metabolism of many drugs including codeine which converts it into morphine

70
Q

Does CYP2D6 have different variants, and how may this affect drug metabolism

A

A variant can affect CYP2D6 metabolism - poor, intermediate and rapid (normal) and ultra-metabolisers

There is the functioning allele, the decreased functioning allele and non-functional allele

Tamoxifen is not efficient with non-functional CYP2D6

71
Q

What does warfarin do

A

Inhibits vitamin K reductase

Upside: reduces thrombosis - treats DVT/PE/AF etc

Downside: reduces thrombosis - bleeds

Narrow therapeutic window

72
Q

What factors can affect warfarin metabolism

A

Drugs
Food
Pharmacogenomics - vit K reductase and CYP2C9, and VKORC1 G>A mutation

73
Q

What are the two isomers of warfarin and their potency

A

R and S
R is not potent, while S is potent

S is metabolised by CYP2C9

74
Q

Describe vitamin K involvement with warfarin

A

Vitamin K is important to activate vitamin K carboxylase which activates clotting factors

Vitamin K reductase replenishes vitamin K

Thus a problem in vitamin K reductase indirectly prevents vitamin K carboxylase activating the clotting factors

Warfarin inhibits vitamin K reductase

75
Q

What are the CYP2C9 variants

A

CYP2C9 *1 = wildtype

CYP2C9 *2/3 = virtually inactive

10% of Caucasians have *2 and *3 thus require smaller doses

76
Q

What is VKORC1

A

Vitamin K Reductase

77
Q

What mutation in VKORC1 reduces vitamin K reductase expression

A

G>A

78
Q

What are the consequences of VKORC1 mutation

A

Reduces expression of Vitamin K reductase

They only just manage to replenish reduced Vitamin K

No consequences in healthy subjects
But warfarin requirement is lower

79
Q

What is 5-flurouracil

A

5-fluorouracil (5FU) or capecitabine = drugs to treat cancers, breast, head and neck, anal, stomach, colon
Can have life threatening toxic effects

80
Q

What does DYPD protein do

A

DPYD protein is essential to process the 5FU or capecitabine during cancer treatment

81
Q

What are the consequences of DYPD deficiency

A

5FU or capecitabine builds up causing more severe toxic effects than usual

Must test prior to chemotherapy to either see reduced dose, or if you should not use at all

82
Q

What are the toxic effects of 5-FU with DYPD deficiency

A

Toxic effect - nausea, vomiting, inflammation of GI tract, decreased RBC production and more

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