Personalised Medicine Flashcards
What is a personalised medicine
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”
Define pharmacogenetics and pharmacometabonics
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
What is the stratified medicine and precision medicine
Stratified medicine: overlapping with personalised medicine, large group of patients that are divided into sub groups to target those individuals
What technology is out there for making sense of genetic information to read DNA
- Sanger sequencing- gold standard- gene analysed for variant of disease reading gene by gene- tendency for someone to develop disease
- Microarray technology: gain whole gene sequence reads which is commercially available in UK and assess and evaluate people’s tendency to develop disease
- Next generation sequencing
Describe Dideoxy chain termination sequencing
- 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
- Stop DNA copying and attach a chemical dye you can read on a sequencing machine
- Can obtain a chromatogram to get a very high resolution copy of DNA- read out the genes
What is microarray analysis and give an example of when it is used
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
Describe the microarray analysis method
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
How does microarray relate to oncology?
- Mutations in genes linked to cell survival and cell proliferation play a central role in oncogenesis
- Provides a key link between mutagens and cancer
- Identifying DNA changes can be crucial for diagnosis and in choice of treatment
What are the 6 main hall marks of cancer
Sustaining proliferative signalling
Evading growth suppressors
Activating invasion and metastasis
Enabling replicative immortality
Inducing angiogenesis
Resisting cell death
What are the emerging hall marks and enabling characteristics
Emerging hallmarks
- Deregulating cellular energetics
- Avoiding immune destruction
Enabling characteristics
- Genome instability and mutation
- Tumor promoting inflammation
What is germline risk
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
What are somatic mutations found in tumours
Mutations that occur during a patients lifetime that directly lead to oncogenesis
- Mutations that occur after birth- individual changes to DNA
What is the direction cancer treatment is heading vs what it is now?
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
Describe BRCA1 in relation to cancer
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
What techniques are used to detect mutations in BRCA1 and BRCA2
Denaturing high performance liquid chromatography
DNA chips
Direct sequencing
Protein-truncation test
How do you target BRCA1 in cancer
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
What is PARPs role in BRCA1
Binds to DNA and allows recognition in breaks in DNA
What is Olaparib
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
Describe heterogeneity in patients with adenocarcinoma of the lung according to driver oncogenes?
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
Describe the EGF receptor
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
What is gefitinib
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
What is Erlotinib
Directly target kinase domain of EGFR receptors
What is a good treatment method to target multiple receptors
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
What is a good treatment method to target single receptors
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
