Anti-angiogenesis Flashcards
Activation of which transciptional complex is considered a critical step in initiating the “angiogenic switch”?
hypoxia inducible factor -1
What endopeptidases are involved in the degradation of extracellular matrix components (ECM)?
matric metalloproteinases (MMPs)
Which pathways are activated by VEGFR
MAPK and PI3K/Akt
Which cell surface receptors are implicated in cell fate, differentiation, and proliferation and what are their ligands?
The notch receptor
the ligands are transmembrane receptors from neighbouring cells - jagged and delta-like ligand (Dll)
What’s the MOA of currently approved drugs that target VEGF pathways?
VEGFR inhibitors
What are the most frequent and/or severe toxicities of VEGFR inhibitors?
- hypertension = most frequent
- proteinuria
- thrombosis, hemorrhage
- GI fistula/ perforation
- poor wound healing
- and reversible posterior leukoencephalopathy
What’s the MOA of bevavizumab?
it’s recombinant humanized monoclonal immunoglobulin G that binds and neutralizes the VEGFR
What are some advantage/ disadvantage of TKI for anti-angiogenesis?
TKI = oral, shorter T 1/2, may target other TKI that are involved in tumour pathogenesis or resistance
Disadvantage: lower target affinity, more promiscuous activity
What’s the MOA of sorafenib?
- targets the ATP binding site of multiple VEGF
- can also target Raf kinase, PDGFR, c-kit, etc
- important for tumour angiogenesis, proliferation, and metastasis
What are some mechanisms of resistance of VEGF inhibition?
- not necessarily a mutation in the target
- can be upregulation of VEGFR, alternative activation of angiogenesis, or adaptation to live in hypoxic environment
- can still have persistent VEGFR dependence despite progression (ie. change to another class of angiogenesis inhibitor can may still work)
- antianiogenesis –> increases hypoxia –> upregulation of HIF 1A –> induction of proangiogenic pathways (VEGF, FGFR, MET, and AXL)
How is sorafenib metabolized?
primarily by the liver and excreted in the feces
Which angiogenetic inhibitor has shown efficacy as a single agent - Moab or TKI?
TKI, but has toxicities of both VEGFR and TKI inhibition
Moab can’t be used alone, so will also need to consider chemo toxicities
What’s the MOA of sunitinib?
TKI, of various receptors
play a key role in tumor growth, angiogenesis, and metastatic progression
What’s the metabolism of sunitinib?
Hepatic, predominately on CYP450 and CYP3A4
majority is eliminated in the feces
watch when used concurrently with drugs that also use CYP3A4
What are some inhibitors of P450?
clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, goldenseal, and grapefruit
What are some inducers of P450?
Phenobarbital, Phenytoin, Rifampicin, St. John’s Wort, Glucocorticoids, Carbamazepine, Dexamethasone, and Taxol.
What is vascular normalization?
small, tortuous, inefficient and leaky tumour vessels are selectively destroy improved blood flow through the tumour as a whole
What’s an example of a veterinary TKI that has anti-angiogenetic activity?
Palladia/ toceranib (VEGFR, PDGFR, Kit, CSF-1, and Flt-3)
- masitinib doesn’t target VEGFR, but does target PDGFR
What’s the outcome of PDGFR inhibition?
Disruption of signaling pathway for blood vessel support structures ex. stromal pericyte component of larger vessel
Does that drug need to target a angiogenetic pathways to disrupt angiogenesis?
no
What are some common angiogenic inhibitor supplementations?
Dogs: thrombospondin-1 mimetics- ABT-526 & ABT-510
has shown some efficacy
What’s the outcome of a phage vector delivering tumour necrosis factor (RGD-A-TNF) to αV intergrin on tumour endothelium?
Partial remission in 2/14 and stable disease in 6/14 dogs with tumour
What was the outcome of inhibitors of matric metalloproteinase (MMP) for canine OSA after doxorubicin?
did not see improvement in overall survival
How does piroxicam help with anti-angiogenesis in canine iUC?
it’s associated with reduced urinary concentrations of the proangiogenic growth factor basic fibroblast growth factor (bFGF) and induction of apoptosis
