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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
How do signal transduction inhibitors work
It blocks the activity of molecules that participate in signal transduction
26
How do gene expression modulators work
It modifies the function of proteins that play a role in controlling gene expression
27
How do apoptosis inducers work
It causes cancer cells to undergo apoptosis
28
How do angiogenesis inhibitors work
They block the growth of new blood vessels to tumours
29
How do immunotherapies work
They trigger the immune system to destroy cancer cells
30
What are the molecular classifications of targeted therapies
Small molecule inhibitors | Monoclonal antibodies
31
Describe small molecule inhibitors
These interfere with the extracellular signalling of tyrosine kinases Found in EGFR and BGF receptors as transmembrane receptors but others can be intracellular
32
What are tyrosine kinases and what does their activation lead to
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
33
How are small molecule inhibitors administered and manufactured
Usually administered orally Chemically manufactured - cheaper than monoclonal antibody production
34
What are the benefits and drawbacks of small molecule inhibitors
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
Describe how monoclonal antibodies work
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
What are the benefits and drawbacks of monoclonal antibodies
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
What are 2 examples of small molecule inhibitors and their uses/targets
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
What is the BCR-ABL oncogene product and what are its effects
``` 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
What is imatinib's mechanism of action
Imatinib occupies the TK active site, leading to decreased protein activity Cross effects to some other TK enzymes
40
What is erlotinib's mechanism of action
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
What is non-small cell lung cancer
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
What is EGFR (HER1)
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
What receptors are involved in the HER group
• 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
Give some examples of monoclonal antibody therapies
Ipilimumab - CTLA-4 Nivolumab and pembrolizumab - anti-PD1 | Trastuzumab (Herceptin) and Pertuzumab - HER2+ breast cancer
45
What conditions does Ipilimumab, Nivolumab and Pembrolizumab treat
Melanoma, hepatocellular cancer, MSI-H colorectal cancer, urothelial carcinoma, head and neck cancer, Classical Hodgkin Lymphoma, Renal Cell Carcinoma and NSCLC
46
What are the roles of CTLA-4 and PD-1
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
What is the role of HER2
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
What are some examples of other targeted cancer therapies
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
Describe how PARP inhibitors work
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
Describe how tamoxifen works in breast cancer
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
Describe how abiraterone and enzalutamide works for mCRPC
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
When is enzalutamide and abiraterone prescribed
Enzalutamide is prescribed in combination with Docetaxel chemotherapy with abiraterone prescribe it this doesn't work
53
Describe CAR-T cell therapy
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
Sources of variation in drug response
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
What is pharmacogenomics
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
What responses to drugs can genetic differences influence
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
What are the benefits of pharmacogenetics
Best outcome - benefit, and no toxicity
58
What current factors can stratify patients into groups for a given disease
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
How can you apply pharmacogenetic knowledge
Understand how the gene variant effects a drug response and whether you should Adjust dosage Choose a different drug
60
Pharmacokinetics V pharmacodynamics
Pharmacokinetics = absorption, distribution, metabolism and excretion Pharmacodynamics - receptors, ion channels, enzymes, immune system
61
Describe hypersensitivity reaction (HSR) to Abacavir
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
Describe what azathioprine does
It is a pro-drug for 6MP - blocks purine metabolism, kills WBCs
63
State azathioprine's benefits and its drawbacks
Upside: Treats leukaemia and inflammatory disease (IBD) Downside: Kills you from sepsis as too much = not enough WBC's
64
How can you tailor azathioprine dosage to genetics
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
What are the phases of pharmacological metabolism
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
What does clopidogrel do
Prevents platelet activation - hence reduces arterial thrombosis Important drug for MI - 20% reduction in events
67
How is clopidogrel transported
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
What are the allelic variants for CYP2C19 - and what risks may an individual face with a given variant
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
What is CYP2D6
An enzyme, part of the CYP450 subfamily, that helps excretion and metabolism of many drugs including codeine which converts it into morphine
70
Does CYP2D6 have different variants, and how may this affect drug metabolism
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
What does warfarin do
Inhibits vitamin K reductase Upside: reduces thrombosis - treats DVT/PE/AF etc Downside: reduces thrombosis - bleeds Narrow therapeutic window
72
What factors can affect warfarin metabolism
Drugs Food Pharmacogenomics - vit K reductase and CYP2C9, and VKORC1 G>A mutation
73
What are the two isomers of warfarin and their potency
R and S R is not potent, while S is potent S is metabolised by CYP2C9
74
Describe vitamin K involvement with warfarin
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
What are the CYP2C9 variants
CYP2C9 *1 = wildtype CYP2C9 *2/3 = virtually inactive 10% of Caucasians have *2 and *3 thus require smaller doses
76
What is VKORC1
Vitamin K Reductase
77
What mutation in VKORC1 reduces vitamin K reductase expression
G>A
78
What are the consequences of VKORC1 mutation
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
What is 5-flurouracil
5-fluorouracil (5FU) or capecitabine = drugs to treat cancers, breast, head and neck, anal, stomach, colon Can have life threatening toxic effects
80
What does DYPD protein do
DPYD protein is essential to process the 5FU or capecitabine during cancer treatment
81
What are the consequences of DYPD deficiency
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
What are the toxic effects of 5-FU with DYPD deficiency
Toxic effect - nausea, vomiting, inflammation of GI tract, decreased RBC production and more

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