Personalised Medicine

Question 1

What is a personalised medicine

Answer 1

The individualisation of healthcare

Use of genetic and biomarker information to predict an individuals risk of disease or to select the most effective and safest treatment

“the right drug, for the right patient, at the right dose”

Question 2

Define pharmacogenetics and pharmacometabonics

Answer 2

Pharmacogenetics:
Genetics and genome information on how an individual will react - workshop from last year

Pharmacometabonics- metabolism patterns of individual to tailor that drug to that individual

Question 3

What is the stratified medicine and precision medicine

Answer 3

Stratified medicine: overlapping with personalised medicine, large group of patients that are divided into sub groups to target those individuals

Question 4

What technology is out there for making sense of genetic information to read DNA

Answer 4

1. Sanger sequencing- gold standard- gene analysed for variant of disease reading gene by gene- tendency for someone to develop disease
2. Microarray technology: gain whole gene sequence reads which is commercially available in UK and assess and evaluate people’s tendency to develop disease
3. Next generation sequencing

Question 5

Describe Dideoxy chain termination sequencing

Answer 5

1. Chemistry of nucleic acids to copy and interrupt copying of DNA by inserting dioxynucleotides- removing extra hydrogen of the nucleotides that prevent proliferation of DNA
2. Stop DNA copying and attach a chemical dye you can read on a sequencing machine
3. Can obtain a chromatogram to get a very high resolution copy of DNA- read out the genes

Question 6

What is microarray analysis and give an example of when it is used

Answer 6

Use of microchips to identify single base pair changes- polymorphisms that are associated with disease (small set of them) you can basically wash and extract DNA on those small sets of them

Example: Ancestry.com

Question 7

Describe the microarray analysis method

Answer 7

Purification:
Aqueous phase: mRNA
Phenol phase Protein and DNA

Coupling:
Cy dyes, DNA, labeled DNA

Hybridisation and washes

Scanning- filter and laser

Normalisation and analysis

Question 8

How does microarray relate to oncology?

Answer 8

1. Mutations in genes linked to cell survival and cell proliferation play a central role in oncogenesis
2. Provides a key link between mutagens and cancer
3. Identifying DNA changes can be crucial for diagnosis and in choice of treatment

Question 9

What are the 6 main hall marks of cancer

Answer 9

Sustaining proliferative signalling

Evading growth suppressors

Activating invasion and metastasis

Enabling replicative immortality

Inducing angiogenesis

Resisting cell death

Question 10

What are the emerging hall marks and enabling characteristics

Answer 10

Emerging hallmarks

• Deregulating cellular energetics
• Avoiding immune destruction

Enabling characteristics

• Genome instability and mutation
• Tumor promoting inflammation

Question 11

What is germline risk

Answer 11

Variants present in an individuals genome since conception that increase risk of developing cancer
- DNA inherited from parents that are present in all cells of your body

Question 12

What are somatic mutations found in tumours

Answer 12

Mutations that occur during a patients lifetime that directly lead to oncogenesis
- Mutations that occur after birth- individual changes to DNA

Question 13

What is the direction cancer treatment is heading vs what it is now?

Answer 13

Heading towards more personalised diagnostics

Present day: one treatment fits all, subset of patients may be affected well, others do not react and cancer spreads

Question 14

Describe BRCA1 in relation to cancer

Answer 14

It has a genetic influence on certain cancers such as breast cancer

Increased family rate of cancer type

Germline alternation that is inherited generation to generation to cause increased risk

Associated with developing tumours, invasive ovarian cancer

1/10 breast cancer patients have BRCA1 mutation

Role: involved in DNA repair, where they repair and replace mistakes made in DNA replication

Question 15

What techniques are used to detect mutations in BRCA1 and BRCA2

Answer 15

Denaturing high performance liquid chromatography

DNA chips

Direct sequencing

Protein-truncation test

Question 16

How do you target BRCA1 in cancer

Answer 16

Target the individual with the tumour with BRCA1 mutation gene

Analyse DNA in cells to see mutation in BRCA1 Kinase called PARP

Target PARP for cancers with BRCA1 mutation gene

Question 17

What is PARPs role in BRCA1

Answer 17

Binds to DNA and allows recognition in breaks in DNA

Question 18

What is Olaparib

Answer 18

Used for maintenance treatment of relapsed platinum sensitive, BRCA mutation

In positive ovarian, fallopian tube and peritoneal cancer after response to second line or subsequent platinum based chemo

Only given to individuals with positive BRCA1 mutations

Question 19

Describe heterogeneity in patients with adenocarcinoma of the lung according to driver oncogenes?

Answer 19

Can involve EGFR or
Number of different genes involved and linked like ALK and KRAS in lung cancer

Mutation of each gene is linked to oncogenesis

Individual base pair changes in DNA- larger rearrangements and deletions alter genes in much wider way

Somatic mutations in cancer- occurs in small subsetted cells- driven by exposure to mutagens and gone to replicate in tumour

Question 20

Describe the EGF receptor

Answer 20

Sits on the outside of the cell which causes a cascade of cells to proliferate or shut down proliferation

Responds to epidermal growth factor (EGF) that responds to cell growth

When EGF receptor is activated, kinase domain will phosphorylate that activates proteins down the cell to affect proliferation

Question 21

What is gefitinib

Answer 21

A kinase domain (enzymatic domain) that transfers phosphate onto proteins to control pathways

Arranges small molecule inhibitors that are screened in-vitro to target kinase

Question 22

What is Erlotinib

Answer 22

Directly target kinase domain of EGFR receptors

Question 23

What is a good treatment method to target multiple receptors

Answer 23

Combine drugs that target multiple pathways against down streamed pathways of drugs that can target these

Target them with a basket of drugs to stop tumour progressing

Question 24

What is a good treatment method to target single receptors

Answer 24

Analysing individual tumours and their response to therapy, break apart individuals that are most likely to respond well

TKI- tyrosine kinase can target them with best drug groups so they are introduced to remission

Question 25

What is CDK 4/6 involved in

Answer 25

Kinase deeply involved in cell replication process

Question 26

What is palbociclib for

Answer 26

Regulates protein at G1 and kinase- prevents cells dividing uncontrollably

Affects Ras/Raf pathway- downstream of EGF receptor

Inhibition of proliferation of luminal oestrogen receptor positive human breast cancer cells line in vitro
- Can be used as an aromatase inhibitor in HER2 negative locally advanced or metastatic breast cancer

Mechanism: kinase inhibitor that binds to ATP binding pocket of CDK46 that prevents it from working
- Aromatase (oestrogen synthase) inhibitor