Precision Medicine 2 Flashcards
1
Q
How would we give precision medicine to cancer patients?
A
- Isolate tissue, and isolate control tissue
- Sequence both samples
- Look at differential mutation and expression patterns between both to find mutations that are present in cancer tissue which are not found in control tissue
- Those will be the candidates for drugs that will selectively affect those pathways
- Deliver those drugs indiviudally in tailored manner on demand
- However, very expensive!
2
Q
Cancer and precision medicine vs traditional approach
A
- Traditional: prescribing the same treatment regimen & drugs to most patients with the cancer type
- Usually starts with surgical removal of tumour, then adjuvant chemo, then radiotherapy
- Some patients have successful treatment whilst others do not - may not be effective for the mutation they have etc, varying effects, never the same
- Precision medicine will give a more personalised treatment by looking for biomarkers, stratifying patients into groups and moving forward, individualising the Rx (precision)
3
Q
What is BRCA1 and what is its role in cancer
A
- Gene variant in BRCA1 very common in patients with breast cancer
- Genes encoding for BRCA1 protein are located on chromosome 17
- Follow up studies: only 12% of patients have normal variants of BRCA1 and 2 in cancer
- Specific inherted mutations in BRCA1 and BRCA2 genes increase risk of breast & ovarian cancers
4
Q
BRCA1 gene and function & its link with retinoblastoma suppressor protein
A
- BRCA1: human tumour suppressor gene (aka caretaker gene) responsible for repairing ds breaks in RNA
- If non-mutated and active in cells, it will negatively control proliferation
- BRCA1 gene is upstream of retinoblastoma protein
- If mutated, activity of retinoblastoma is lower, increasing risk of further mutations as there is a lack of regulation of progression through the cell cycle
- Regulated progression through cell cycle ensuring correct cell division and growth
- Involved in regulation of apoptosis in damaged cells
5
Q
Targeting BRCA1 & role of PARP
A
- PARP enzyme essential for DNA repair
- PARP plays a role in DNA repair that is regulated by BRCA1
- If PARP is inhibited in non cancerous cells, cell will survive
- If inhibited in heterogenous cells (one healthy and one mutated various) , tumours will persist
- If there are two mutations, cell will be selective to inhibition
- Thus if we know the genetic set up of the patient, we can use this drug to selectively suppress proliferation of tumours
- Inhibiting its enzyme activity with drugs achieves synthetic lethality by preventing unwanted DNA repair in the treatment of cancers = cancer death
6
Q
Example of a drug available ot target BRCA1
A
Olaparib
7
Q
Olaparib MoA
A
- PARP inhibitor
- PARP is a protein that helps damaged cells to repair themselves
- Cancer cells with BRCA mutations rely on PARP to keep their DNA healthy
- Thus if PARP is inhibited, the cancer cells will die
- Genetic screening before prescribing to ensure two mutations in BRAC1/BRCA2 (only effective in this case)
8
Q
Mutations in Endothelial Growth Factor Receptor in cancer
A
- GF required for cell to grow, and later on to induce cellular proliferation
- When EGF bind to R, it stimulates a series of phosphorylation events, then the signal is transduced further down in the cell resulting in proliferation and survival
- Ras also involved in this process
- If no EGF present in surrounding cell, Ras is inactive so usually does not proliferate
- Mutations in EGFR very common in cancer = affecting phosphorylation events
- In many mutated forms, mutation results in CONSTITUTIVE activity of receptor - receptor then signals down to Ras and activates signalling pathways that leads to proliferation
9
Q
Name two drugs that are EGFR inhibitors and their target
A
- Gefitinib
- Erlotinib
- Both are EGFR inhibitors with tyrosine kinase as their tagret
- Inhibiting mutated EGFR-TK will prevent uncontrolled proliferation
10
Q
Define wild type mutation
A
- Gene found in its natural non-mutated form
11
Q
K-Ras mutations & targeting EGFR & cetuximab
A
- Mutations in K-ras define the response to cetuximab
- Remember, Ras is downstream of EGFR
- Cetuximab is only effective if the tumour has wild type K-ras - genetic testing required prior to prescribing!
- This is because mutated Ras doesn’t require active EGFR to signal - even if we inhibited EGFR, therapy would not be effective because Ras would still be constitituvely active
12
Q
Cetuximab MoA
A
- Recombinant Mab that binds to and inhibits the activity of EGFR in patients with wild-type K-Ras
- Reduced cell proliferation
- Genetic testing needed to ensure no K-ras mutations prior to prescribing to ensure effective therapy
13
Q
Cell cycle dependent kinase 4/6
A
- CDK are regulators of the cell cycle; ensuring cells progress through the cycle
- NF-kB, Ras, CDK etc and other pathways positively influence the acitivty of CDK (which explains why the genetic set ups in many cancers can be diff but still have the same cellular consequences)
- Mutations in CDK 4 & 6 = uncontrolled cell growth
14
Q
Palbociclib
A
- Selective inhibtor of CKD 4 and 6
- Only prescribe if they are mutated!
- Will slow down cancer progression through cell cycle therefore slow down growth
- Expensive - only prescribed if company provides the discount agreed in patient access scheme
15
Q
How do mRNA vaccines work
A
- Introduce RNA in cell (injection)
- It will be translated by ribosomes
- It is then digested in proteasome and presented on MHC molecules on surface of cell
- Parts of this artifically introduced protein will be released from cell into surrounding
- Body will recgonise free protein as foreign - triggers immune system to recognise it, produce Abs and remove protein
- If our cells that have produced that protein, they will present it on the surface of the cells and the immune system will see them as being infected - they will be targetted by killer cells and actively removed from system
