8 - Targeted therapy Flashcards
Targeted therapy
Monoclonal antibodies
Small tyrosine kinase inhibitors
What are targeted cancer therapies
drugs or other substances that block the growth and spread of cancer by interfering with specific molecules involved in tumour growth and progression
How does tyrosine kinase receptors work
GF binds to the binding domain
Activates the MAPK and P13 kinase pathway
Growth, survival and motility
How can biological therapies inhibit cancer
Antibody inhibitors of growth factors bind to the growth factor to prevent growth signal
- antibody-drug conjugates target drug to tumour cells
-u
human
-zu
humanised 95%
- xi
chimeric 65% human
How to inhibit tyrosine kinase receptors
Antagonise ligand-receptor signalling
inhibit the dimerisation
EGFR
cetuximab
panitumumab
HER2
Trastuzumab
HER3
Pertuzumab
VEGFR
Bavacizumab
How do antibodies access tumour cells
Tumour cells have leaky blood vessels
no lymph drainage
antibodies can accumulate
How to MoAbs kill the tumour directly
Signalling blocked
Apoptosis induced
Delivery of toxic payload
How do MoAbs kill tumour via immune mediated mechanisms
Phagocytosis
Complement dependent cytotoxicity
Antibody dependent cell
Cytotoxicity ASCC
MoA of herceptin (trastuzumab)
Attaches to HER2 tyrosine kinase receptor
Inhibits dimerisation so signalling pathways not activated
ADCC - NK cell binds to the MoAb and destroys the tumour cell
Targeting the VEGFR
Inhibits angiogenesis
What is VEGF needed for
Formation of nascent blood vessels
Protects endothelial cells from death via activation of PKC pathway and upregulation of anti-apoptotic proteins
What occurs when blocking VEGF
Inhibits tumour growth and metastasis
Deprives tumours of nutrient providing blood vessels
What are small molecule tyrosine kinase inhibitors
target oncogene product
e.g getfitinib
Which tyrosine kinase domain is associated with drug resistance
EGFR
TKI
First generation tyrosine kinase inhibitors (reversible)
Erlotinib
Gefitinib
Second generation EGFR tyrosine kinase inhibitors (irreversible)
Afatinib
Third gen EGFR tyrosine kinase inhibitors (Mutant-selective)
Osimertinib
