Pharm: Targeted Therapy Flashcards
Trazstuzumab is used to combat what cancer?
What receptor does it bind to?
What is its effector mechanism?
TRASTUZUMAB
Use against HER2/NEU + breast cancers.
(Remember, that’s a tyrosine kinase, EGFR2)
It binds directly to HER2/NEU and inhibits stimulation by EGF. This causes the receptor to b down regulated.
p27 accumulates, and leads to cell cycle arrest.
What does PERTUZUMAB do?
Blocks the heterodimerization of HER2 and HER3
Her2 kinase usually phosphorylates the HER3 cytoplasmic domain and leads to kinase cascade and cell proliferation
What 2 MABs block EGFR1/HER1 and prevent its activation?
PANITUMUMAB and CETUXIMAB
You want to get initiated into EGFR (sounds like a frat), so you wear pants and a tux.
What MAB drug binds CTLA-4?
Describe the effector mechanism of this drug.
IPILUMUMAB
Works as an immunostimulant. Binds to CTLA-4 receptor on T-cells, preventing its binding with B7 (CD80)
Tregs don’t work, so mass proliferation of T-cells results.
INDIRECT MECHANISM -T-cell mediated anti-tumor immune response.
What MAB can be used specifically against B-cell cancers? (Lymphoma)
RITUXIMAB
What is the mechanism of RITUXIMAB
Binds CD20 on B-cells
Rapid, sustained B-cell depletion
What does BEVACIZUMAB do?
VEGF inhibitor: No angiogenesis for SOLID TUMORS
HIF-1a is able to translocate to the nucleus under anoxic conditions (usually it’s broken down by proteosome).
It causes the synthesis of VEGF, but BEVACIZUMAB binds VEGF and sequesters its action.
How does a MAB drug cause ADCC?
MABs are based on IgG antibodies, so they can induce ADCC in NK cells.
What are the 4 basic mechanisms of killing by a MAB?
- Complement-mediated cytoxcicity
- ADCC
- Activation of Apoptotic signals
- Deliver a cytotoxic agent to the cells.
A mutation in what part of a Tyrosine Kinase receptor would effect the efficacy of a TKI?
ATP binding-site - highly conserved between types of Tyrosine Kinase Receptors. All TKIs on the market today work by binding to this site.
WHat kind of residue within the ATP-binding site serves as the “Gatekeeper?” What is the significance of this residue?
A threonine residue in the ATP binding site is altered by many cancers,
What effect does a mutation in the ATP binding site of a Tyrosine Kinase receptor have in the efficiency of a TKI drug?
It DOES NOT prevent the drug from binding completely. Instead, it ALTERS THE POTENCY and shifts the dose/response curve to the right.
Need MORE of the drug to produce the same effect as before the mutation.
Also narrows the therapeutic window
What is the route of administration of TKIs?
Oral - TKIs are small molecule drugs and can be absorbed through the GI tract
(Not IV injection like MABs.)
If you have a KRAS or BRAF mutation, will a TKI work?
No! KRAS and BRAF oncogenes are downstream in the EGFR pathway, among others (cross-talk).
If these genes have a GOF mutation, then their proliferative pathways are constitutively ON, regardless of the presence of EGF ligand or the MAB.
Drugs that end in “OLIMUS” do what?
Name the drugs
mTOR inhibitors.
SIROLIMUS, EVEROLIMUS, TEMSIROLIMUS.
Just remember -olimus.
