Genomics and Personalised Medicine Flashcards
What factors can influence drug interactions
Demographics e.g. Age, sex leading to different body composition
Comorbidities - chronical renal failure = reduced clearance of drugs
Environment -diet, smoking, air pollutions
Drug-drug interactions - directly or through inhibition of other drug metabolising enzymes
Drug-food interactions
Genomic variation
Other omics - transcriptomics
How does genomics help personalised medicine
Novel therapies - gene therapy to deliver tailor made treatments to cells
Identify new targets for therapy
Optimise existing medicine through drug repurposing, guiding treatment decisions and dosing predicting resistance
What is a CAR-T cell
T cell with a chimeric antigen receptor - designed to a specific target
What is the goal of CAR-T cells with CD28 and what are the drawbacks
Enables it to co-stimulate and activate other CAR-T cells
However rapid activation and killing can cause cytokine release syndrome and high inflammation
Treated with drugs treating inflammation such as IL-6 inhibitors
What is CD28
CD28 helps to activate CD8+ T cells
In contrast, activation can be inhibited by CTLA-4 and PD1
What is the long-term goal of CAR-T cells
T cells to develop into memory cells
What is cystic fibrosis
Cystic fibrosis is an AR disease caused by defect in the CF transmembrane conductance regulator (CFTR)
This results in lack/impaired function of a chloride channel that results in thickened sticky secretions infected the airways and GI tract and may lead to reduced fertility
Why do symptoms occur as a result of a defect in CFTR in CF
Defective ciliary clearance leading to airway obstructions
Altered inflammatory response by impaired immune cell function
This leads to an inflammatory response which leads to a cycle of inflammation, obstruction and infection
Poor clearance also affects the male reproductive system
What are 2 new treatments for CF
Gene therapy and CFTR modulators
What are the subtypes of CFTR variants
Severe = Type 1 - no protein, Type 2 - no traffic to site needed, Type 3 - no function
Most are Type 2 = ΔF508
Milder - Type 4 - less function, Type 5 - less protein, Type 6 - less stable
What are CFTR modulators
There are ‘correctors’ which can help push/traffic these receptors to the cell surface
Potentiators can help the opening of the receptor to allow chloride flux
Give an example of a repurposed drug - what it was used for and what it can be used for now
Imatinib - initially used for gastrointestinal stromal tumours (GIST)- a tumour of connective tissue
Now it is used in chronic myeloid leukaemia targeting the BCR-ABL fusion gene
How does the BCR-ABL gene lead to CML
Ubiquitous activation of ABL cytosine kinase
This leads to excess proliferation of myeloid cells and inhibition of apoptosis
How does imatinib target the BCR-ABL protein
Imatinib can bind to the ATP binding site as a small molecule inhibitor
This stops phosphorylation of its substrates, stopping the excess growth of white cells
What does imatinib target in gastrointestinal stromal tumours
KIT gene and PDGFRA
What does the KIT gene do
KIT gene encodes a transmembrane receptor for a growth factor called stem cell factor
What do mutations in KIT cause
Mutations occur in the area encoding the intracellular domain on exon 11, which act as tyrosine kinase receptors to activate other enzymes
This means it is always activated even without stem cell factor = increased cell division
Why may codeine become toxic in some individuals
Codein can be metabolised 3 ways
33% = norcodeine = not active 60% = codeine-g-glucuronide = partially active 10% = CYP2D6 = morphine
But if CYP2D6 metabolism is increased there is too much morphine = opioid toxicity
What are the phases of drug metabolism
Drugs and toxins, as well as endogenous molecules such as prostacyclin’s, bile acids and cholesterol undergo phase I reaction in the liver to make them more polar mainly by CYP450
Phase II allows conjugation to make them more water soluble
Elimination is predominantly via urine and kidneys, also bile, sweat, saliva and lungs
What is the CYP450 family
These are enzymes which contain iron (haem), and are located in the endoplasmic reticulum of hepatic cells
What are the substrates of the CYP450 family
They have many substrates, including common medicines such as caffeine, paracetamol, codeine, tamoxifen, warfarin, antibiotics, antidepressants
CYP450 enzymes are codominant - what does this mean
The level of function depends on the combination of alleles
Two genes impaired = poor metaboliser
One normal, one impaired = intermediate
Two normal = extensive/normal
Patient can have duplicated gene = 3 normal genes = ultra-rapid metaboliser
What is melanoma
Melanoma is a skin cancer developing in melanocytes which forms moles in 25% of cases
What are the genetic and environmental risk factors for melanoma
UV light
BRAF gene - an intermediate messenger in the epidermal growth factor pathway for cell proliferation
What does the BRAF gene do
BRAF is a key intermediate messenger in the epidermal growth factor/MAP kinase/cell proliferation pathway - variants can cause downstream activation
What is a drug used to treat BRAF mutated melanoma
Vemurafenib
Why can malignant melanoma evolve resistance
Malignant melanoma has a rapid cell turnover thus high mutational burden
This is due to selective pressures leading to different tumours (clonal heterogeneity), distinct populations and different responses to treatment in a single cancer population!
