targeting the hallmarks of cancer

Question 1

why target the hallmarks

Answer 1

you can target the tumour and not the healthy cells

Question 2

targeting angiogenesis: monoclonal antibodies

Answer 2

bind to VEGFR (on endothelial cells) to block VEGF binding, work outside the cell

Question 3

targeting angiogenesis: tyrosine kinase inhibitors

Answer 3

block the activation of VEGFR on endothelial cells, they work inside the cell on the phosphorylated kinase domains of the VEGFR

Question 4

most widely used antibody blockade for angiogenesis

Answer 4

bevacizumab (anti-VEGF)

Question 5

bevacizumab impact on tumour growth

Answer 5

decreases rate of tumour growth (tumour still grows tho)

Question 6

resistance to anti-angiogenic therapy: induction of hypoxic pro-survival signalling

Answer 6

in hypoxic conditions, HIF1α is stabilised and so translates into the nucleus and heterodimerised with its partner protein HIF1β

Question 7

what happens to HIF1α

Answer 7

it is hydroxylated by prolyl hydroxylase (but oxygen is required for this) and ubiquitinated and then degraded

Question 8

what are the effects of targeting HIF1α and VEGF

Answer 8

there is a decrease in growth rate but the tumour still grows

Question 9

resistance to anti-angiogenic therapy: increased via alternative mechanisms

Answer 9

in response to a lack of blood vessels, the tumour produces more growth factors and more VEGF, so targeting 1 molecule is not enough

Question 10

what is EGFR

Answer 10

epidermal growth factor receptor, its expressed on the cell membrane of many human cancers

Question 11

what growth factors are released by tumours when there has been a block of angiogenesis (5)

Answer 11

PlGF (placental growth factor), ANG1&2 (angiopoietin 1&2), FGFs (fibroblast growth factor), G-CSF (granulocyte colony-stimulating factor) and SDF1 (stromal cell-derived factor 1)

Question 12

what happens when ligands (e.g. EGF) bind to EGFR

Answer 12

the receptor is activated and a signal transduction cascade that regulates cell proliferation is triggered

Question 13

what does inhibition of EGFR result in

Answer 13

inhibition of growth and proliferation of many EGFR +ve tumours

Question 14

what is the cascade when a ligand binds to EGFR

Answer 14

the intracellular kinase domain is activated which activates intracellular kinase cascades like RAS, RAF, MEK, ERK pathway or the PI3kinase, AKT, mTOR pathway. At the end of the pathways are TFs which are translocated to the nucleus and they increase the expression of genes modulating the hallmarks

Question 15

what tumours show an overexpression of EGFR (4)

Answer 15

colon, head + neck, pancreatic and NSCLC (non small cell lung cancer)

Question 16

biomarkers for EGFR

Answer 16

take section of tumour and analyse it using antibodies

Question 17

when does EGFR inhibition not work

Answer 17

when EGFR is not expressed

Question 18

2 ways of targeting EGFR

Answer 18

Monoclonal antibodies (MAb) or Tyrosine kinase inhibitors (act on the intracellular kinase domain)

Question 19

how are MAb used to target EGFR

Answer 19

they target the external domain of EGFR, they are specific to EGFR and its heterodimers. They inhibit EGFR phosphorylation and signal transduction cascade

Question 20

targeting sustained proliferation: De Novo mutation resistance

Answer 20

in response to inhibition of EGFR there are mutations to RAS, RAF or PI3K which trigger a signalling cascade anyway so sustained proliferative signalling continues