Targeted Therapy Basics Flashcards
What are targeted therapies?
- Chosen to act on specific molecular targets
- Cytostatic - block tumour cell proliferation
- Personalised medicine
Wheras chemotherapies are cytotoxic to all rapidly dividing cells, normal or cancerous.
What are the hallmarks of cancer?
- Evade growth supressors
- Avoid immune system destruction
- Immortal
- Inflammation promoting tumour growth
- Invasion
- New blood vessle growth
- Genetic instability
- Resist apoptosis
- Alter cell metabolism in favour of cell growth
- Ongoing signals to tell cells to keep growing
What drugs can prevent cancer cells evading growth supressors?
Cyclin-dependent kinase inhibitors
e.g.
Riboclib
Palbociclib
Abemaciclib
What drugs prevent cancer cells avoiding destruction by the immune system?
Immune activating anti-CTLA4 mAb
Ipilimumab
Treleimumab
What drugs prevent cancer cells being immortal?
Telomerase inhibitors
Tamoxifen
Azidothymidine
What are some examples of targeted therapies? (7)
- Hormone therapies
- Signal Transduction Inhibitors
- Gene expression modulators
- Pro-apoptosis agents
- Angiogenesis inibitors
- Immunotherapies
- Toxin delivery molecules - monoclonal antibodies that deliver toxic molecules to cause cell cancer death
What is the role of growth factors?
- Growth factors bind to and activate Receptor Tyrosine Kinases on the cell surface
- RTKs with growth factors bound to them ‘pair up’ (dimerise)
- Dimerisation activates the ‘kinase’ activity. ATP releases phosphate groups which bind to them.
- Phosphate group binding activates docking sites for proteins
- When proteins bind to the docking sites they are activated
- Signal transduction cascade is initiated
- Signal transduction cascade activates transcription factors
- Activated transcription factors results in downstream target gene activation
There are natural inhibitors throughout this pathway
In normal cells these are interactions between neighbouring cells which tell cells that all is well and to stay alive.
In a cancer cell this tells the cell to ignore DNA damage and grow and proliferate even though the DNA is faulty.
How can cancer inappropriately activate the growth factor pathway?
- Receptor gene amplification causes receptor proteins to be overproduced
- Receptor gene mutation causes the receptor to be over-active
- Signalling molecules in the cascade could be mutated and over-active and act without activation
- Natural inhibitors along the pathway are lost, ineffective or silenced
- Transcription factors are overproduced
How does inappropriate activation of the growth factor pathway lead to cancer?
- Constant cell growth (despite DNA errors)
- Resistance to chemo or radiotherapy
- Enhanced survival /resistane to apoptosis
- Angiogenesis promotion
- Metastases
Which targeted drugs interfere with this inappropriately activated growth factor cascade?
- Monoclonal Antibodies (mabs)
- Small molecule kinase inhibitors (nibs)
How do monoclonal antibodies (mabs) act as targeted therapies?
Large proteins that bind to specific proteins on the surface of cancer cells (which are absent or low in normal cells)
- Block activation of receptors e.g. EGFR targeted antibodiy Cetuximab (colon and H&N cancer)
- Bind to growth factors to prevent them from binding to receptors e.g. VEGF antagonist, Bevacizumab
- Cause an immune response
- Attract WBCs e.g. Rituximab (anti-CD20)
- Inhibit signals that prevent immune cells from attacking the body’s own tissues e.g. ipilimumab or nivolumab
Can be used in combination with chemo and radiotherapy
Given by injection as are destroyed by stomach acid, last weeks- months in the body
How do Small Molecule Kinase Inhibitors (nibs) act as targeted therapies?
Tiny molecules that penetrate the cell membrane to act on targets within the cell.
Tyrosine kinases can be too active or levels of them be too high - blocking them is a pharamceutical target.
Kinase inhibitors mimic ATP shape competing to active sites of the receptor. Quite imprecise.
Can be given orally, last in the body hours-days.
