17th annual symposium for...with anti‐vegf/vegfr therapies. the moa of ang‐2 contribution to...
TRANSCRIPT
PAGE 1 of 35 – © H.G.Augustin
17th Annual Symposium for ANTI-ANGIOGENESIS AND IMMUNE THERAPIES FOR
CANCER
PAGE 2 of 35 – © H.G.Augustin
Angiopoietin/Tie signaling:
A strong target for anti‐
angiogenic intervention?
Hellmut G. Augustin, DVM, PhD
German Cancer Research Center &
Heidelberg University
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Angiopoietin-2 as a target for tumor therapy
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Angiopoietin-2 as a target for tumor therapy
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Angiopoietin-2 as a target for tumor therapy
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Angiopoietin-2 as a target for tumor therapy
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Antiangiogenic therapies account today for >15% of the global
oncology drug market.
Anti‐VEGF/VEGFR prolongs overall survival by approx. 25%.
The absolute gain of overall survival is in months.
Anti‐VEGF/VEGFR does not work as monotherapy.
Anti‐VEGF/VEGFR synergizes with chemotherapy.
Anti‐VEGF/VEGFR does not just lead to vessel regression,
but also induces normalization of patent vessels.
Robust stratifying angiodiagnostic procedures with prognostic
and predictive value have not yet been established.
Punchline: Status quo of anti-VEGF/VEGFR therapy
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Pre
vent
ion
PTK-787Control
Inte
rven
tion
Intervention protocol: Allow human vascular network to grow in mice for 20 days – followed by 10 day treatment with VEGFR blocker PTK/ZK.
Alajati et al.: Nature Methods, 2008
0
20
40
60
80
+‐PTK‐787:
MVD/m
m2
pericyte‐covered
no pericytecoverage
*
Anti-VEGF/VEGFR MOA: Pruning of the immature vasculature
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sprouting angiogenesisVEGF/VEGFR
remodelingphalanx cells
quiescentphalanx cells
stalk cells tip cell
Anti-VEGF/VEGFR-induced pruning leads to vessel normalization
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sprouting angiogenesisVEGF/VEGFR
remodelingphalanx cells
quiescentphalanx cells
stalk cells tip cell
Anti-VEGF/VEGFR-induced pruning leads to vessel normalization
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sprouting angiogenesisVEGF/VEGFR
remodelingphalanx cells
quiescentphalanx cells
stalk cells tip cell
Anti-VEGF/VEGFR-induced pruning leads to vessel normalization
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sprouting angiogenesisVEGF/VEGFR
vessel maturationAngiopoietin/Tie
remodelingphalanx cells
quiescentphalanx cells
stalk cells tip cell
Angiopoietin/Tie signaling controls vessel remodeling and maturation
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AMGEN
AERPIOARRAY BIOPHARMA
COMPUGEN
COVX/PFIZERASTRA ZENECASANOFI/REGENERONROCHEZYNGENIA
Number
of publications
40.000
30.000
20.000
50.000
VEGF Angiopoietin
10.000
0
Gerald et al., Cancer Res., 2013
Ang/Tie signaling: Among the least well understood vascular RTKs
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TIE2
ANG‐1TIE‐1 ANG‐2
Vascular morphogenesis through the Angiopoietin/Tie system
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Made by endothelial cells
Stored in endothelial cells (Weibel‐Palade bodies)
Fiedler et al., Blood 2004
Transcriptionally dramatically regulated
Hegen et al.: ATVB, 2004
Helfrich et al., Clin Cancer Res, 2009
Key facts: Angiopoietin-2
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Made by endothelial cells
Stored in endothelial cells (Weibel‐Palade bodies)
Fiedler et al., Blood 2004
Transcriptionally dramatically regulated
Hegen et al.: ATVB, 2004
Helfrich et al., Clin Cancer Res, 2009
Facilitator of EC responses to exogenous cytokine.s‐ Permeability‐ Inflammation‐ Promotes angiogenic switch‐ Facilitates metastasis
Fiedler et al., Nat Med, 2006
Nassare et al., Cancer Res, 2009
Im et a., Int J Cancer, 2013
Benest et al., Plos One, 2013
Key facts: Angiopoietin-2
PAGE 18 of 35 – © H.G.Augustin
Made by endothelial cells
Stored in endothelial cells (Weibel‐Palade bodies)
Fiedler et al., Blood 2004
Transcriptionally dramatically regulated
Hegen et al.: ATVB, 2004
Helfrich et al., Clin Cancer Res, 2009
Facilitator of EC responses to exogenous cytokine.s‐ Permeability‐ Inflammation‐ Promotes angiogenic switch‐ Facilitates metastasis
Fiedler et al., Nat Med, 2006
Nassare et al., Cancer Res, 2009
Im et a., Int J Cancer, 2013
Benest et al., Plos One, 2013
Mechanistically: Ang‐2 is the functional antagonist of Ang‐2 by acting as partial agonist‐ Ang‐2 transgene phenocopies Ang‐1 KO.‐ Ang‐2 transgene expression in EC quenchesTie2 phosphorylation.
Key facts: Angiopoietin-2
PAGE 19 of 35 – © H.G.Augustin
Made by endothelial cells
Stored in endothelial cells (Weibel‐Palade bodies)
Fiedler et al., Blood 2004
Transcriptionally dramatically regulated
Hegen et al.: ATVB, 2004
Helfrich et al., Clin Cancer Res, 2009
Facilitator of EC responses to exogenous cytokine.s‐ Permeability‐ Inflammation‐ Promotes angiogenic switch‐ Facilitates metastasis
Fiedler et al., Nat Med, 2006
Nassare et al., Cancer Res, 2009
Im et a., Int J Cancer, 2013
Benest et al., Plos One, 2013
Mechanistically: Ang‐2 is the functional antagonist of Ang‐2 by acting as partial agonist‐ Ang‐2 transgene phenocopies Ang‐1 KO.‐ Ang‐2 transgene expression in EC quenchesTie2 phosphorylation.
Ang‐2 stimulates angiogenesis by signaling through integrins in Tie2 negative angiogenic EC
Felcht et al., J Clin Invest, 2012
Key facts: Angiopoietin-2
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vascular normalization on stalk/phalanx cells
antiangiogenicon tip cells
Anti‐Ang‐2 sharpens the vascular normalization gradient
Benefits of Ang-2 targeting therapies and synergy with anti-VEGF
Gerald et al., Cancer Res., 2013
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Ang-2 promotes early stages of tumor growth but is dispensable for later stages of tumor progression
CANCER RESEARCH 69: 1324‐33, 2009
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Nasarre et al., Cancer Res, 2009
Tum
or w
eigh
t [g
]
*
0.0
0.5
1.0
1.5
Ang-2 -/-wild type
Ang-2 -/-wild type
Time [d]
Tum
or v
olum
e [c
m3 ]
0 5 10 15 20 25
0.5
1.0
1.5
Ang-2 -/-wild type
0.0
Ang-2 promotes early stages of tumor growth but is dispensable for later stages of tumor progression
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vessel density pericytecoveragetumor growth
Kienast et al., Clin Cancer Res, 2013 (Roche)
Ang2/VEGF combination therapy
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Vessels
Merged
Ang2‐WTAng2‐/‐
50 µm 50 µm
Im et al., Int. J. Cancer, 2013
Effect of host Ang-2 on metastatic colonization: liver metastasis
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Postsurgical anti-Ang-2 adjuvant therapy in Lews lung carcinoma
Srivastava, Hu et al., Cancer Cell, 2014
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! "
#! "
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( ! "
) ! "
*! "
+! "
Me
an m
eta
stat
ic lu
ng f
ract
ion
IgG AntiAng-2
SacrificedPost
Surgery
***
Anti-Ang-2 adjuvant therapy limits postsurgical lung metastasis
Srivastava, Hu et al., Cancer Cell, 2014
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Anti-Ang-2IgG
1.0
2.0
3.0
4.0
(x10
6 p/s/c
m2/sr)
vess
el c
ount
/FO
V
% p
eric
yte
cove
rage
Postsurgical anti-Ang-2 therapy in orthotopic breast cancer 4T1
Srivastava, Hu et al., Cancer Cell, 2014
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An
ti-A
ng-
2Ig
G
Anti-Ang-2 therapy limits osteolytic bone metastasis
Srivastava, Hu et al., Cancer Cell, 2014
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(x107
p/s/cm
2/sr)
MTD MET
Anti-Ang-2
IgG
Met Chemo+Anti-Ang-2
2.0
0.5
1.5
1.0
2.5
Low-dose metronomic chemotherapy synergizes with anti-metastatic action of anti-Ang-2 in 4T1 tumor metastasis
Srivastava, Hu et al., Cancer Cell, 2014
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Combination therapy provides maximum survival advantage
Srivastava, Hu et al., Cancer Cell, 2014
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Low-dose metronomic chemotherapy synergizes with anti-metastatic action of anti-Ang-2 in LLC tumor metastasis
Srivastava, Hu et al., Cancer Cell, 2014
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Bone marrow Ovarian follicles
Body weight
Combination therapy has less adverse effects compared to MTD
Srivastava, Hu et al., Cancer Cell, 2014
PAGE 34 of 35 – © H.G.AugustinSrivastava, Hu et al., Cancer Cell, 2014
Model of Ang-2 MOA during metastatic progression
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Ang‐2 acts as a master switch of vascular responsiveness facilitating the
response of endothelial cells to multiple cytokines.
Anti‐Ang‐2 therapies target sprouting tip cells and remodeling stalk
cells. They sharpen the vascular normalization gradient and synergize
with anti‐VEGF/VEGFR therapies.
The MOA of Ang‐2 contribution to metastatic colonization warrants a
reconsideration of anti‐angiogenic combination therapies (anti‐Ang‐2
and anti‐VEGF) together with LDMC as a safe and effective postsurgical
adjuvant tumor therapy.
Tie1 is a very promising, yet understudied receptor.
Summary
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HEIDELBERGUNIVERSITY
Junhao HuKshitij SrivastavaSusanne Bartels
Claudia Korn
Stephanie Kapel
Carolin Mogler
Anja Runge
Matthias Wieland
Collaborators
Manfred Jugold (DKFZ)
Ruth Muschel (Oxford)
Manolis Pasparakis (Cologne)
Hans-Reimer Rodewald (DKFZ)
Markus Thomas (Roche)
Gavin Thurston (Regeneron)
Thanks to….