Cancer And Drugs Flashcards
What is cancer and what are the most common cancers
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
What are the four stages of cancer progression
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
What health alterations occur as a result of cancer
Genomic - mutation, loss/gain, promoter methylation
Protein - mutant form, overexpression
Pathways - activated cell survival, loss of apoptotic cells
Biology - limitless replication, angiogenesis, tissue invasion
What are the factors to consider when treating cancer
Clinical implementation of NGS
Conduction of bio marker clinical trials
Finding of predictive markers for immunotherapy and precision immunooncology
Tumour heterogeneity and resistance
Why should we consider clinical implementation of NGS in cancer
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
Why should we consider conducting bio marker driven clinical trials for cancer drugs
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
Why should you consider tumour heterogeneity and resistance when treating cancer
The capacity to study heterogeneity and study mutations that may confirm resistant to treatment can help decide the most appropriate treatment for that patient
Why should you consider predictive markers for immunotherapy and precision immunooncology when treating cancer
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
What was the traditional view of cancer progression and development including the primary characteristics, treatment and agents
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
What is topoisomerase
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.
What is the modern view of cancer including its primary characteristics and treatment
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
Compare chemotherapy and targeted therapies
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
What is the breast cancer traditional diagnosis TNM system
TNM System
T = tumour size, 1-4 N = lymph node status, 0-3 M = metastasis, 0-1
What are the breast cancer traditional histopathological types
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
What is the breast cancer traditional diagnosis grade system
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
What is the breast cancer traditional diagnosis within immunohistochemistry
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
Describe the modern breast cancer diagnosis
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
Describe the treatment decisions within lung cancer
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
Describe the aims and priorities of the 100K and genome
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
What is the primary characteristic of cancer
Specific locations drive cell division (clonal heterogeneity) with selected pressures
Antigenicity, growth rate, hormones, cytotoxic drugs, capacity for invasion and metastasis
What are driver mutations
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
What are targeted cancer therapies
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
What categories of targeted therapies are there
Targeted therapies include surgery, chemotherapy, radiation therapy and hormone therapy
What are the 5 different modes of action of targeted cancer therapies
Signal transduction inhibitors Gene expression modulators Apoptosis inducers Angiogenesis inhibitors Immunotherapies
How do signal transduction inhibitors work
It blocks the activity of molecules that participate in signal transduction
How do gene expression modulators work
It modifies the function of proteins that play a role in controlling gene expression
How do apoptosis inducers work
It causes cancer cells to undergo apoptosis
How do angiogenesis inhibitors work
They block the growth of new blood vessels to tumours
How do immunotherapies work
They trigger the immune system to destroy cancer cells
What are the molecular classifications of targeted therapies
Small molecule inhibitors
Monoclonal antibodies
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
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
How are small molecule inhibitors administered and manufactured
Usually administered orally
Chemically manufactured - cheaper than monoclonal antibody production
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
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)
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
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
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
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
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)
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
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)
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
Give some examples of monoclonal antibody therapies
Ipilimumab - CTLA-4 Nivolumab and pembrolizumab - anti-PD1
Trastuzumab (Herceptin) and Pertuzumab - HER2+ breast cancer
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
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
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
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
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
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
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
When is enzalutamide and abiraterone prescribed
Enzalutamide is prescribed in combination with Docetaxel chemotherapy with abiraterone prescribe it this doesn’t work
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
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
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?
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
What are the benefits of pharmacogenetics
Best outcome - benefit, and no toxicity
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)
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
Pharmacokinetics V pharmacodynamics
Pharmacokinetics = absorption, distribution, metabolism and excretion
Pharmacodynamics - receptors, ion channels, enzymes, immune system
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
Describe what azathioprine does
It is a pro-drug for 6MP - blocks purine metabolism, kills WBCs
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
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
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)
What does clopidogrel do
Prevents platelet activation - hence reduces arterial thrombosis
Important drug for MI - 20% reduction in events
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
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
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
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
What does warfarin do
Inhibits vitamin K reductase
Upside: reduces thrombosis - treats DVT/PE/AF etc
Downside: reduces thrombosis - bleeds
Narrow therapeutic window
What factors can affect warfarin metabolism
Drugs
Food
Pharmacogenomics - vit K reductase and CYP2C9, and VKORC1 G>A mutation
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
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
What are the CYP2C9 variants
CYP2C9 *1 = wildtype
CYP2C9 *2/3 = virtually inactive
10% of Caucasians have *2 and *3 thus require smaller doses
What is VKORC1
Vitamin K Reductase
What mutation in VKORC1 reduces vitamin K reductase expression
G>A
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
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
What does DYPD protein do
DPYD protein is essential to process the 5FU or capecitabine during cancer treatment
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
What are the toxic effects of 5-FU with DYPD deficiency
Toxic effect - nausea, vomiting, inflammation of GI tract, decreased RBC production and more
