Genomics and Personalised Medicine

Question 1

What factors can influence drug interactions

Answer 1

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

Question 2

How does genomics help personalised medicine

Answer 2

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

Question 3

What is a CAR-T cell

Answer 3

T cell with a chimeric antigen receptor - designed to a specific target

Question 4

What is the goal of CAR-T cells with CD28 and what are the drawbacks

Answer 4

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

Question 5

What is CD28

Answer 5

CD28 helps to activate CD8+ T cells

In contrast, activation can be inhibited by CTLA-4 and PD1

Question 6

What is the long-term goal of CAR-T cells

Answer 6

T cells to develop into memory cells

Question 7

What is cystic fibrosis

Answer 7

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

Question 8

Why do symptoms occur as a result of a defect in CFTR in CF

Answer 8

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

Question 9

What are 2 new treatments for CF

Answer 9

Gene therapy and CFTR modulators

Question 10

What are the subtypes of CFTR variants

Answer 10

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

Question 11

What are CFTR modulators

Answer 11

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

Question 12

Give an example of a repurposed drug - what it was used for and what it can be used for now

Answer 12

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

Question 13

How does the BCR-ABL gene lead to CML

Answer 13

Ubiquitous activation of ABL cytosine kinase

This leads to excess proliferation of myeloid cells and inhibition of apoptosis

Question 14

How does imatinib target the BCR-ABL protein

Answer 14

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

Question 15

What does imatinib target in gastrointestinal stromal tumours

Answer 15

KIT gene and PDGFRA

Question 16

What does the KIT gene do

Answer 16

KIT gene encodes a transmembrane receptor for a growth factor called stem cell factor

Question 17

What do mutations in KIT cause

Answer 17

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

Question 18

Why may codeine become toxic in some individuals

Answer 18

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

Question 19

What are the phases of drug metabolism

Answer 19

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

Question 20

What is the CYP450 family

Answer 20

These are enzymes which contain iron (haem), and are located in the endoplasmic reticulum of hepatic cells

Question 21

What are the substrates of the CYP450 family

Answer 21

They have many substrates, including common medicines such as caffeine, paracetamol, codeine, tamoxifen, warfarin, antibiotics, antidepressants

Question 22

CYP450 enzymes are codominant - what does this mean

Answer 22

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

Question 23

What is melanoma

Answer 23

Melanoma is a skin cancer developing in melanocytes which forms moles in 25% of cases

Question 24

What are the genetic and environmental risk factors for melanoma

Answer 24

UV light

BRAF gene - an intermediate messenger in the epidermal growth factor pathway for cell proliferation

Question 25

What does the BRAF gene do

Answer 25

BRAF is a key intermediate messenger in the epidermal growth factor/MAP kinase/cell proliferation pathway - variants can cause downstream activation

Question 26

What is a drug used to treat BRAF mutated melanoma

Answer 26

Vemurafenib

Question 27

Why can malignant melanoma evolve resistance

Answer 27

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!