Angiogenesis 2

Question 1

anti-angiogenic therapy

Answer 1

“does not aim to destroy tumours, but instead by limiting their blood supply it attempts to shrink tumours and prevent them from growing”

Question 2

5 classes of angiogenic antagonists

Answer 2

• inhibitors of proteases
• inhibitors of endothelial cell migration and proliferation
• inhibitors of angiogenic growth factor
• inhibitors of matrix proteins on endothelial cell surface, such as integrins and copper
• inhibitors with unique mechanisms

Question 3

anti-VEGF therapies

Answer 3

• monoclonal antibodies directed against specific proangiogenic growth factors or their receptors
• small molecule tyrosine kinase inhibitors of multiple proangiogenic growth factor receptors

Question 4

bevacizumab

Answer 4

monoclonal antibody against VEGF-A

Question 5

ramucirumab

Answer 5

monoclonal antibody to VEGFR-2

Question 6

monoclonal antibody to VEGFR-2

Answer 6

tyrosine kinase inhibitors that target VEGF receptors

Question 7

process of VEGF binding

Answer 7

VEGF binds to receptor -> receptor dimerisation and autophosphorylation -> production of various proangiogenic factors

Question 8

ANTI-VEGF

Answer 8

• bevacizumab
• recombinant anti-VEGF MAb
• T 1/2 = 14-21 days
• neutralises all forms of VEGF

Question 9

Side effects of bevacizumab

Answer 9

• hypertension
• proteinuria
• gi perforations
• bleeding

Question 10

alfibercept

Answer 10

• protein comprised of segments of the extracellular domains of VEGFR1 and VEGFR2
• fused to constant region (Fc) of human IgG1
• functions as soluble decoy receptor, binds VEGF and prevents it binding to actual VEGF receptor

Question 11

protein kinases

Answer 11

• catalyse transfer of gamma phosphate from ATP to one of more amino acid residues in a protein substrate side chain
• results in conformational change, affecting protein function

Question 12

tyrosine kinase inhibitors structure

Answer 12

• ligand binding extracellular domain
• single transmembrane domain
• cytosolic tyrosine kinase domain
• flexible C-terminal tail

Question 13

how RTK inhibitors work

Answer 13

• phosphorylation sites that promote TKD activation present in juxtamembrane domain, activation loop and C-terminal tail
• activation loop resides within active site of TKD thus sterically hindering access by ATP to nucleotide-binding pocket
• phosphorylation of activation loop promotes conformational changes, inducing swinging out of activation loop which releases auto-inhibition effects as well as stabilising activated TKD

Question 14

NRTKs (non-receptor tyrosine kinases)

Answer 14

• subgroup of tyrosine kinases, intracellular cytoplasmic proteins or anchored to membrane of cell
• 9 subfamilies according to sequence similarities
• each NRTK family defined according to sequence homology of kinase domain

Question 15

how sorafanib works

Answer 15

• inserts into hydrophobic pocket within catalytic loop of RAF-1
• prevents receptor kinase from binding ATP and phosphorylating their respective tyrosine target residues
• targets ATP binding domain and competes with ATP

Question 16

sorafanib issues

Answer 16

• potency of sorafenib becomes lower and lower due to resistance development
• extremely expensive

Question 17

thalidomide

Answer 17

• was originally marketed as a sedative
• since tissues are most sensitive to thalidomide when undergoing growth, extreme birth defects in pregnant women taking thalidomide
• thalidomide inhibits angiogenesis at that stage
• apoptogenic for neovasculature

Question 18

how thalidomide works

Answer 18

• binds to cereblon, a ubiquitin ligase
• degrades numerous targets, mostly zinc finger-containing transcription factors
• efficaciously inhibits pro-angiogenic factors

Question 19

factors thalidomide inhibits

Answer 19

factors thalidomide inhibits

Question 20

limitations of anti-angiogenic therapy

Answer 20

• cannot irradiate tumours as a stand-alone strategy
• prolonged administration reduces microvascular density within tumours, compromising delivery of chemo to tumour cells
• is a very complex process involving many growth factors and cellular processes

Question 21

hallmarks of resistance to antiangiogenic therapy

Answer 21

• growth factor redundancy
• recruitment of bone marrow-derived cells
• local stromal cells
• vessel co-option and vasculogenic mimicry
• increased metastasis
• other emerging mechanisms

Question 22

• growth factor redundancy
• recruitment of bone marrow-derived cells
• local stromal cells
• vessel co-option and vasculogenic mimicry
• increased metastasis
• other emerging mechanisms

Answer 22

• macugen
• ranibizumab
• bevacizumab
• aflibercept

Question 23

how do anti-VEGF therapies treat diabetic retinopathy and macular degeneration

Answer 23

• drug injected into vitreous of the eye and passes into sub retinal space where vessels proliferate
• neovascularization is then blocked, preventing bleeding into retina

Question 24

do all drugs require intravitreal injection?

Answer 24

no