Appel Flashcards
What are the two types of targeted therapies?
Tyrosine Kinase inhibitors and Monoclonal Antibodies
What IS targeted therapy?
Drug targets biological process that is measurable and correlates with clinical outcome. drug is less toxic to normal cells.
What is the MOA of Imatinib?
Occupies the ATP binding pocket of the Abl kinase domain. Prevents substrate phosphorylation and signaling.
How do monoclonal antibodies work?
Bind to ligands or receptors interrupting essential cell processes. carry lethal radioisotope or toxin. Recruit host immune factors including NK cells and complement cascade.
What is VEGF?
Vascular endothelial growth factor… activates blood vessel growth. Tumor uses to recruit a blood supply!
Bevacizumab MOA?
Binds directly to the VEGF ligand and prevents activation of receptors to inhibit angiogenesis.
(mab)
FOR METASTIC DISEASE
What is the major difference between the actions ofmonoclonal ABs and TKIs?
TKIs are much less specific!
bind intracellularly! also have a longer half life and metabolized by p450
Why is sunitinib a dirty molecule?
Targets LOTS! vegf, pdgf, c-kit, flt-3
Sunitnib MOA?
TKI! inhibits signal transduction intracellularly, chiefly vegr-2…. inhibits endothelial cell migration, prolif, differentiation, survival, vessel permeability.
Sunitinib is most often indicated for….?
Kidney Cancer!
WHat are the drugs that target angiogenesis? both MAB and TKI
Imatinib, Bevacizumab, Sunitinib
Why target the EGFR axis?
In tumor cells, EGFR-TK signal is inappropriately turned on! activity drives uncontrolled growth.
What is the most common anti EGFR TKI?
Erlotinib!!
Lung cancer
tox- rash + diarrhea
What is the MOA for cetuximab?
High affinity Ab binds to EGFR to block ligand induced phosphorylation of EGFR. blocks cell prolif and promotes apoptosis.
tox- rash with pustules
COLORECTAL CANCER
Which monoclonal antibody binds to the HER2 extracellular domain?
Trastuzumab! prevents activation of HER2’s intracellular tyrosine kinase.
decreased signaling decreases prolif, adhesion, migration, differentiation.
for BREAST CANCER
How can we predict Trastuzumab response?
We can measure HER2 overexpression!
Lapatinib?
Oral! inhibits intracellular signaling by HER1 and HER2! ADVANCED BREAST CANCER
What drug offers a dual blockade in advanced breast cancer?
Pertuzumab~
heterodimerization and homodimerization (her2 and3)
What is the mechanism of Rituximab?
Antibody dependent cell mediated cytotoxicity (ADCC) Induces B cell death, anti-CD20 monoclonal antibody! (cd20 on PRE-B)
LYMPHOMA!!!!!
How do we choose a target antigen?
Should be highly expressed in tumor cells, NOT expressed in normal cells, present on SURFACE, should be internalizing
Antibody should be…?
specific to target, limited immungenecity, have good affinity
Linker should be…
stable in circulation so not released systemically into normal cells! should bind agent until ADC internalized!
