Lecture 6: Anti-angiogenic therapy

Question 1

What is the phylosophy of anti-angiogenic therapy ?

Answer 1

To ‘starve’ the tumor to death by blocking its blood supply

Question 2

What is the name of an anti-VEGF monoclonal antibody drug ?

Answer 2

Bevacizumab

Question 3

Steps of tumorigenesis of pancreatic islets in RIP-Tag mice

Answer 3

• Normal state
• Hyperplastic/dysplastic stage
• Angiogenic state (transition to malignancy)
• Tumor stage

Question 4

Consequences of VEGFA KO (4)

Answer 4

• Increased hypoxia (loss of vessels)
• Loss of endothelial cells
• Reduced islet proliferation
• Altered apoptosis patterns

Question 5

What are the three types of trials and their question ?

Answer 5

• Prevention trial : can angiogenic switch be prevented ?
• Intervention trial : can tumor progression be slowed or stopped ?
• Regression trial : can tumor growth be stabilized or regressed and lifespan be extended
  (déso c’est long)

Question 6

Is the VEGFR inhibitor effective for each trial ?

Answer 6

Yes for PT and IT no for RT

Question 7

What is the role of pericytes towards the vasculature ?

Answer 7

Pericytes support and protect the endothelial cells of the tumor (and normal tissue) vasculature

Question 8

What does the role of pericytes entail for vessels ?

Answer 8

Limited effect of VEGF/VEGFR inhibitors on pericyte covered vessels

Question 9

Role of PDGF inhibitors

Answer 9

Dissociate pericytes from tumor endothelial cells (no supportive function anymore), allow VEGF/VEGFR inhibitors to kill tumor endothelial cells

Question 10

What can a multi-kinase inhibitor (which hits both VEGFR and PDGFR) do ?

Answer 10

Impair angiogenesis, reduce vascularity and disrupt pericyte coverage

Question 11

Name of a multi-kinase inhibitor

Answer 11

Sunitinib

Question 12

Two aspects of cancer that Sunitinib improves

Answer 12

Survival and tumor burden

Question 13

Effect of blocking ANG II on tumors ?

Answer 13

• Fewer endothelial cells
• Large necrotic areas
• Mature vessels (more ANG I, vessel normalization)

Question 14

Overall effect of angiogenesis inhibitors

Answer 14

Demonstrable but transitory benefits, after which
tumors start growing again (progression)

Question 15

Two modes of resistance tumors have to angiogenesis inhibitors

Answer 15

• Adaptive (Evasive resistance)
• Intrinsic non-responsiveness

Question 16

How does evasive resistance work ?

Answer 16

Up-regulating alternative pro-angiogenic signaling circuits to promote re-vascularization

Question 17

What happens at the same time as re-vascularization ?

Answer 17

Tumor re-growth

Question 18

What induces re-vascularization ?

Answer 18

Hypoxia induced during the response induces angiogenesis, which induces re-vascularization

Question 19

How is angiogenesis induced even without VEGF ?

Answer 19

Other pro-angiogenic factors are up-regulated, possibly in a hypoxia-dependent manner

Question 20

What are Brivanib and Sorafenib ?

Answer 20

Brivanib: VEGF and FGF inhibitor
Sorafenib: VEGF and PDGF inhibitor

Question 21

How can we more effectively and stably inhibit angiogenesis ?

Answer 21

Block VEGFR/PDGFR and FGFR

Question 22

How can we limit resistance to anti-VEGF therapy ?

Answer 22

Double VEGFR/ANG2 blockade since ANG2 is hypoxia induced and will promote angiogenesis

Question 23

Evasive resistance to angiogenesis inhibitors by… (2 methods)

Answer 23

• Recruitment of pro-angiogenic myeloid cells (macrophages) from the bone marrow
• Increased local invasion and metastasis

Question 24

What is the role of c-Met ?

Answer 24

Controls cell mobility

Question 25

What is the effect of angiogenesis inhibitors on c-Met ?

Answer 25

It is induced, and its phosphorylation is up-regulated (hypoxia-dependent)

Question 26

What treatment includes c-Met ? What does it do ?

Answer 26

Dual inhibition of VEGF/VEGFR and c-Met reduces invasiveness and prolongs survival

Question 27

How do invasion and metastasis evade the necessity for angiogenesis to produce tumor neo-vessels?

Answer 27

By co-opting normal tissue vessels to fuel disseminated tumor growth

Question 28

How do tumors use co-option of normal tissue vessels ?

Answer 28

As a means for cancer cells to access oxygen and nutrients to fuel tumor growth

Question 29

Distinguishing parameters of non-angiogenic vessel co-option (4)

Answer 29

- Infrequent endothelial cell proliferation - No sprouting - Dense coverage by pericytes - Intact basement membrane between endothelial cells and pericytes

Question 30

Different strategy to target tumor vasculature

Answer 30

Vascular normalization : produce vessels with better blood flow, more complete pericyte coverage

Question 31

2 advantages of normalizing the tumor vasculature

Answer 31

- Better delivery of chemo-therapies through the circulation - Better extravasation of T cells into tumors via normalized blood vessels

Question 32

Steps of anti-angiogenic immunotherapy

Answer 32

- Vascular normalization (anti-angiogenesis) - T cell infiltration and reduced suppression - Tumor regression (+ immunitherapy)

Question 33

4 places where cancer cells can go with vessel co-option

Answer 33

- In the air space - Lining the pneumocytes - In the alveolar wall - Around pre-existing large vessels