Download Fun with Angiogenesis

Compensatory Angiogenesis and
Tumor Refractoriness
Prof. Rajesh N Gacche
Tumor Biology Laboratory, School of Life Sciences
SRTM Univeristy, Nanded, India (MS)
Angiogenesis is the formation
of new blood vessels from
preexisting one
Structure of vessels and capillaries
Small artery:
Monocellular layer of endothelial cells
Capillary: endothelial cell,
basal lamina, pericytes
Angiogenesis is regulated by endogenous
activators and Inhibitors
Pro-Angiogenic
factors
Anti-Angiogenic
Anti-Angiogenic
factors
factors
Normal angiogenesis
Normal angiogenesis
Pro-Angiogenic
factors
Anti-Angiogenic
factors
Insufficient
angiogenesis
Pro-Angiogenic
factors
Anti-Angiogenic
factors
Excessive angiogenesis
Process of Tumor Angiogenesis
Regulate
IL-1, IL-6
Cytokines, FGF
VEGF
Induce
Expression of
MMPs
(Matrix
MetalloProteinases)
VEGF, FGF,
PGF, IGF,
Angp, EGF,
HGF, HIF, TGF,
IL-3, IL-8, Ang
VEGF, FGF,
PGDF, PGF,
IGF, Angp,
EGF, HGF, HIF,
TGF, TNF, IL-3,
IL-8, Ang
Tumor
VEGF,
PGDF,
IGF,
Angp
VEGF, PGF,
HIF-1
1. Activation
2. Basement
membrane
degradation
3. Migration
4.
Differentiation
/ Proliferation /
Tube formation
5. Stabilization
/ Maturation
FGF
XL880,
TAK-701,
Relotumumab
Regulation of
Cytoskeleton
AKT Pathway
CDC42
CDC42 Pathway
RAC1 Pathway
RAC1
PI3K
RAS
PLCγ
PIP3
cRAF
VEGFR-Family
PLCγ
SHC
IP3
FAK
DAG
PKC
NOSIII
MEK 1/2
CamK II
PDGF
Paxillin
NO
ERK 1/2
Regorafenib,
Ponatinib
Sorafenib
FGFR
IP3
Pazopanib,
Ranibizumab,
Sunitinib
Brivanib,
Nintedanib,
Pentosan- polysulfate
c-MET
RAS
Ang-1,2,3
PI3K
AKT Pathway
HGF
VEGFFamily
Avastin , Aflibercept,
Pegaptanib,
Tie2/
Tek
PDGFR
PI3K
RhoA
Actin,
Stress
fibres &
Adhesion
Cell Proliferation
Vasodilation/
Permeability
Vav2
PI3K
Vav1
Rac1
Por1
Por2
Lamellipodia
/ Filopoda
Formation
Cell Survival
Cell Migration
Angiogenesis
PIP2
CDC42
N-WASP
PIP3
Caspase 9
PIP2 BAD
Targeting Tumor Angiogenesis for
designing novel drugs
• 3D structural information of angiogenic proteins has
profoundly influenced the philosophy of drug design and
development.
• There have been major and striking advances in protein
crystallography.
• Structures solved by protein crystallography are
exceptionally valuable and forms foundation for effective
ligand design.
• Structural knowledge can be effectively utilized in
developing better therapeutic agents for modulation of
angiogenesis in cancer therapy.
VEGFR-1
Hydrophobic
contacts
These interactions have
opened novel
therapeutic avenues to
study the role of
VEGFR-1-specific ligand
in angiogenesismediated pathologies.
Hydrogen
bonds
VEGF-B
These
contacts can be utilized
in generating peptide
mimetic inhibitor
molecules that can
modulate VEGF-C
interaction with VEGFR-2
VEGFR-2
VEGF-C
FGF-2
These interactions
provide a
structural insight to
design therapeutic
agents that can target
FGF-2::FGFR
interactions.
FGFR
FGF-1
Interactions at interface
of FGF-1::FGFR opens
new avenues for
rational drug design
targeting FGF1-induced
angiogenesis
and cell proliferation.
FGFR
PGDFR
Such biochemical
communications can be
efficiently utilized to
modulate
PGDF β-receptor
interaction in
therapeutic context.
PGDF- β
VEGFR-1
These interactions hold
a key to design strategy
for modulation of PGFVEGFR-1 interaction.
PGF
IGFBP
Interactions at IGFBP
and IGF can guide
development of
interaction based
inhibitors.
IGF
Tie2K
These contacts at ATP
binding site can be
utilized to develop
therapeutically relevant
agents targeting Tie2K
activity.
Biochemical
interactions at
EGF::EGFR interface
possess enormous
potential to develop
contact based
therapeutic agents.
EGF
EGFR
HGF
These interactions at
HGF::c-Met thus
provide an
opportunity to
selectively
modulate HGF activity
as antagonist for
cancer therapy.
C-Met
CBP
HIF
All these interactions
at TGF::EGFR possess
lot of potential to be
therapeutically
targeted.
Interactions at HIFCBP complex can be
extensively used to
develop
small molecule
transcriptional
modulators.
More about structural opportunities for developing
anti-angiogenic agents
Drugs
FDA Approval
Improvement
in PFS
(Months)
Improvement
in OS (Months)
Bevacizumab
metastatic colorectal cancer (with
chemotherapy)
metastatic nonsquamous NSCLC
(with chemotherapy)
advanced cervical cancer (with
chemotherapy)
metastatic RCC (Renal cell carcinoma)
metastatic RCC
metastatic RCC
advanced medullary thyroid cancer
advanced RCC
chemorefractory metastatic colorectal
cancer
4.4
4.7
1.7
2.0
2.3
3.7
6
2.7
5
6.2
2
0.2
4.6
NS
NA
NA
NA
1.4
chemorefractory metastatic colorectal
cancer
2.2
1.4
Cabozantinib
advanced medullary thyroid cancer
Ramucirumab
metastatic gastric and GEJ cancers
Source: Rakesh Jain, Cancer Cell 26, November 10, 2014
7.2
0.8
NS
1.4
Sunitinib
Sorafenib
Pazopanib
Vandetanib
Axitinib
Regorafenib
Aflibercept
Clinical Research in Angiogenesis
Inhibitors
as on 1st Nov 2015
• 3512 Clinical trials are registered
• 1445 Trials have been completed (41 %)
• 356 Trials have been Terminated (10 %)
• 89 Trials have been withdrawn (2.5 %)
• 14 Trials have been suspended (0.4 %)
Source: Clinical Trials.gov
Arguments ?
• Targeting Tumor Angiogenesis: a Right target or
a Wrong Choice ?
• Why the tumors growth is more aggressive after
drug holidays ?
• Why there is evolving drugs resistance towards
anti-angiogenic agents ?
• Does the compensatory angiogenic
mechanisms is the major factors in limiting
the efficacy of anti-angiogenic therapy ?
Targeting
Angiogenesis:
Right
target
or
a
Targeting tumor angiogenesis: an
Wrong
Choice ?
attractive target with
emerging
challenges
Pathophysiologic
al point of view
pharmacological
point of view
• Without
neovascularisation
 No tumor
growth beyond a
size of 2 mm
 No metastasis
How will you supply
an anti-cancer drugs
to the tumor
without an
appropriate blood
supply?
‘Normalization of tumor vasculature’:
a new paradigm by Prof. Rakesh Jain
• Blood vessels of tumor are more complex,
dilated, tortuous, hyperpermeable and
disorganized
• This makes the access of drug molecules difficult
to reach every cell of tumor body.
• Instead of killing the entire tumor vessels, it is
imperative to normalize (organized vessel
complex) it initially?
• Appropriate doses of anti-antiangiogenic drugs
has been shown to normalize the vessels.
Appropriate doses of anti-antiangiogenic drugs has been shown to
normalize the vessels.
Goel S et al. Physiol Rev 2011;91:1071-1121
Inbuilt threats of targeting tumor
angiogenesis
• At present anti-angiogenic agents can not
discriminate between physiological and
pathological angiogenesis.
• Hence, hampers normal angiogenesis.
• Anti-angiogenic agents lack efficacy due to
prevalence of compensatory angiogenesis
pathways.
• Off-target toxicities unrelated to blockade of
physiological angiogenesis………another big
issue!!
Conspiracy of Compensatory
Angiogenesis in acquired drug resistance
• A. VEGF dependent
• B. VEGF independent:
– FGF, PDGF, Angiopetins, Ephrins etc
– DLL4-Notch Signalling
C. Myeoloid & Stromal/Tumor Cell
mediated angiogenic reprogramming.
D. Angiogenesis independent remodeling
mechanisms like vascular mimicry, vessel
cooption and in intussusceptive angiogenesis
Source: Gacche RN, 2015,Oncogenesis (Nature)
VEGF-axis dependent and non-VEGF mediated mechanisms
of resistance to anti-angiogenic therapies
Source: Gacche RN, 2015,Oncogenesis (Nature)
Avastin
FGF
Cell Migration
VEGFR-2
VEGF-D
VEGFR-3
Cell Survival
NOTCH
VEGFR-3
Sustained
Angiogenesis
in VEGFR-2
Inhibition
State
Up regulate
Cell Proliferation
A n g i o g e n e s i s
anti-angiogenic
resistance in VEGFA
targeted therapies
NOTCH Signaling
Synergistic
Inhibition
DLL-4
VEGF – A Signaling
FGFR Signaling
Vasodilatation/ Permeability
Endothelial cell
VEGF-A By pass
Synergistic
activity
FGFR
Proteolytic
cleavage
VEGF-A
VEGF -C
PlGF
VEGF bypass
pathways
Source: Gacche RN, 2015,Oncogenesis (Nature)
Source: Gacche RN, 2015,Oncogenesis (Nature)
Source: Gacche RN, 2015,Oncogenesis (Nature)
Conclusions
• Based on the present clinical and
epidemiological literature it is clear that the
future settings of targeting tumor angiogenesis
should customize more on inhibiting the
compensatory angiogenic pathways/factors so
as to improve the efficacy of anti-angiogenic
agents.
• Developing anti-tumor agents hitting multiple
targets are more appreciated in the midst of
evolving resistance of cancer cells towards
present day anticancer drugs
In silico work of di-, tri-, tetra-, and pentahydroxy substituted flavones
Nanded
Quantum chemical
descriptors
Thank you