Targeted therapies Flashcards
Herceptin/Trastuzumab
Binds HER2 receptor, preventing PI3K/AKT pathway activation
Resistance occurs through use of the k-ras pathway - not dependent on HER2 signalling
Avastin
Ligand inactivator: Binds and inactivates VEGF ligand preventing angiogenesis
Erlotinib
SMI for non-small cell lung cancer
EGFR inhibitor
Resistance develops often due to mutation in ATP binding pocket of EGFR kinase domain
Also amplification of HGFR leading to ERBB3 dependent activation of PI3K (i.e. it takes a different route to activate PI3K)
Imatinib/GLIVEC
BCR-ABL fusion protein inhibitor
This is a truncal mutation (example of oncogenic addiction)
>90% response rate
However, resistance similar to Erlotinib so 2nd generations are being developed
Kadcyla
Herceptin-Emtansine antibody-drug conjugate
Form of targeted chemotherapy for metastatic BrCa
Can overcome resistance
But: £8000 per cycle, patients often require 20+ cycles
Aflibacept
Chimeric (engineered) protein
Acts through ligand deprivation to attract VEGF
Can overcome resistance BUT
No use in ligand independent signalling
Olaparib
Targets DNA repair
PARP inhibitor for use in BRCA mutant BrCa
Traps PARP at SSBs –> inhibits DNA repair; replication fork arrest and DSBs
Mutant BRCA cant repair DSBs through HR so undergoes apoptosis
Cetuximab
Anti-EGFR monoclonal antibody
Only licenced for k-ras wild-type colon cancer
Over expressed K-ras initiates growth signal independent of EGFR signalling (k-ras mutation common in Met Colorectal)
This was the first genetic test to guide treatment of cancer
Sorafenib
HCC
Targets VEGF and Raf-k simultaneously in an attempt to combat signalling redundancy and resistance
Ipilimumab
Anti-CTLA-4
CTLA-4 is a negative regulator of T cell activation
- It prevents co-stimulation via CD28 which is required for T cell activation
Brentuximab vedotin
Antibody against CD30 attached to chemotherapy drug MMAE
