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Antiangiogenics as Chemosensitizers:
Out of the Frying Pan into the Fire?
Dr. Urban Emmenegger
Potential Conflict of Interest
• Consultant / 2008 –
– Amgen
• Research Grant – Consultant / 2007 –
– Novartis
• Research Grant / 2007 –
– Wyeth
Montreal
March 27 & 28, 2009
1st Quebec Conference on Therapeutic
Resistance in Cancer
Antiangiogenics as
Chemosensitizers: Out of the
Frying Pan into the Fire?
Urban Emmenegger, MD
Clinician-Scientist
Sunnybrook Odette Cancer Centre & Research Institute
Sunnybrook Health Sciences Centre
Department of Medicine, University of Toronto
2075 Bayview Avenue, Toronto/ON M4N 3M5, Canada
[email protected]
Disclosure
Consulting Fees: Amgen, Novartis
Research Funding: Novartis, Wyeth
Acknowledgements
Sunnybrook Research Institute
Sunnybrook Odette Cancer Centre
Annabelle Chow
Scott Berry
Edward Chow
Yoo-Joung Ko
Linda Rabeneck
Maureen Trudeau
Bob Kerbel
John Ebos
Giulio Francia
Christina Lee
Tony Mutsaers
Terence Tang
William Cruz
Chris Folkins
Kae Hashimoto
Shan Man
Yuval Shaked
Ping Xu
University of Pisa, Pisa/Italy
Guido Bocci
D. Dumont
M. Julius
Objectives
1) To review basic principles of tumor
angiogenesis and antiangiogenic
therapies.
2) To discuss the rationale for combining
chemotherapy with antiangiogenic
agents as a means to overcome/delay
resistance.
3) To identify challenges of this approach.
Hippocrates… noticed that blood vessels around a malignant tumor looked
like the claws of a crab. He named the disease karkinos (the Greek name for
crab) …
(http://medicineworld.org/cancer/history.html)
Tumor angiogenesis: therapeutic implications
Folkman J. N Engl J Med. 1971;285(21):1182-6
TAF inhibition reverses
this process 3
1
2
Local (sprouting) angiogenesis
Sex hormones
IL-8
PDGFs
VEGF-B
EGF
PlGF
FGFs
Thrombospondin-1/2
Interferon-α
PEDF
Angiostatin
Endostatin
Vasostatin
Tumstatin
Canstatin
Arresten
…
VEGF-C
VEGF-A
VEGF-D
angiogenesis
angiogenesis
angiogenesis
angiogenesis
angiogenesis
The VEGF Family And Its Receptors
PlGF
VEGF-A*
206 VEGF-B
189
165
121
VEGFR-2
(Flk-1/KDR)
VEGFR-1
VEGF-C
VEGF-D
VEGFR-3
(Flt-4)
(Flt-1)
Angiogenesis
‘Inflammation’
*VEGF-A = ‘VEGF’
Angiogenesis
Lymphangiogenesis Lymphangiogenesis
endothelial cell
‘Systemic’ angiogenesis (i.e.,
vasculogenesis)
Kerbel RS. N Engl J Med 2008;358:2039-2049
Agents Targeting the VEGF Pathway
Anti-VEGF
antibodies
Soluble
decoy VEGF
receptors
VEGF
(Bevacizumab)
(VEGF-Trap)
mTOR inhibitors
(Temsirolimus, Everolimus)
P
P
P
P
P
P
VEGFR-1
P
P
AntiVEGFR
antibodies
(IMC-1121b)
VEGFR-2
endothelial cell
Small-molecule
VEGFR kinase inhibitors
(Sunitinib, Sorafenib, Axitinib, Cediranib … )
Sunitinib
VEGFR1-3
PDGFR alpha
PDGFR beta
RET
KIT
FLT-3
Sorafenib
VEGFR1-3
C-/B-RAF
PDGFR beta
RET
KIT
FLT-3
http://www.kinomescan.com/show_data.asp
Vatalanib
Delta-like Ligand 4 - Notch Pathway
Increased
angiogenesis:
functionally
abnormal+++
vasculature
Decreased
angiogenesis:
vascular
rarefaction
reduced blood flow, severe hypoxia reduced blood flow, severe hypoxia
Adapted from Hicklin DJ. Nature Biotechnology 25, 300 - 302 (2007)
‘Accidental’ Anti-Vascular Agents
•
•
•
•
•
•
•
•
•
•
•
•
•
chemotherapeutics
hormonal therapies
radiation therapy
COX-2 inhibitors
corticosteroids
thalidomide
LMW heparins
ACE inhibitors
propranolol
glitazones
doxycyclin
valproic acid
...
Léauté-Labrèze C, N Engl J Med.
2008;358(24):2649-51.
Antiangiogenic Therapies: Phase III Success Stories
2004
2006
Non-small cell lung cancer: Bev + PC (PFS/OS)
2007
1971 Folkman
Hypothesis
1983/89 VPF/VEGF
1997 Bevacizumab
Colorectal Cancer: Bev + FOLFOX (PFS/OS)
Breast Cancer: Bev + Paclitaxel (PFS)
Renal Cell Cancer: Sunitinib (PFS/OS)
Sorafenib (PFS)
Temsirolimus (PFS/OS)
Bev + IFN-alfa 2a (PFS)
2008
Hepatocellular Ca: Sorafenib (PFS/OS)
Renal Cell Cancer: Everolimus (PFS)
Activity of Single-Agent Bevacizumab
Tumor Type (Ref)
Objective SD
RR (%)
(%)
PFS/TTP
(median, m)
Comments
0
-
4
Phase II, n=15,
10 mg/kg q2wks
6.7
16
5.6
Phase I/II, n=75,
3-10-20 mg/kg q2wks
10
-
4.8
Phase II, n=39,
10 mg/kg q2wks
5
20
5
Phase II, n=46,
10 mg/kg q2wks
Recurrent Ovarian
Ca (Burger 05)
18
55
-
Phase II, n=62,
15 mg/kg q3wks
Colorectal Ca (2nd
line) (Giantonio 07)
3.3
-
2.7
Phase III, n=243,
10 mg/kg q2wks
0
-
3
Phase II, n=5,
15 mg/kg q2wks
CR Prostate Ca
(Reese 01)
Met Breast Ca
(Cobleigh 03)
Kidney Ca
(Yang 03)
Recurrent NHL
(Stopeck 05)
Metastatic Melanoma (Varker 07)
Activity of Bevacizumab & Chemotherapy
Ref
Hurwitz
mCRC
1st line
Giantonio
mCRC
2nd line
Sandler
NSCLC
1st line
Miller
ABC
1st line
Tx
IFL
+B
IFL
FOLFOX4+B
FOLFOX4
P-C
+B
P-C
P
+B
P
Median
Survival
(m)
20.3
15.6
12.9
10.8
12.3
10.3
26.7*
25.2*
1y
survival
(%)
74.3
63.4
-
-
51
44
-
-
Median
PFS (m)
10.6
6.2
7.3
4.7
6.2
4.5
11.8
5.9
Overall
RR (%)
44.8
34.8
22.7
8.6
35
15
36.9
21.2
mCRC = metastatic colorectal cancer, NSCLC = non-small cell lung cancer, ABC = advanced breast
cancer, IFL = irinotecan-fluorouracil-leucovorin, FOLFOX4 = oxaliplatin-fluorouracil-leucovorin, P =
paclitaxel, C = carboplatin , B = bevacizumab
Underestimation of the true potential?
• Antiangiogenics developed
without biomarker guidance
for optimal dosing:
– flat dosing common for RTKIs
– various bevacizumab regimens
• Lack of markers for patient
selection
• Challenging integration into
current standards of care
Rationale against Combination Therapy
• Antivascular effects I
– inhibition of neo-angiogenesis
– induction of endothelial cell
apoptosis
– impaired mobilization of CEPs
and other bone marrow derived
cells
– vasoconstriction
de Bazelaire, C. Clin Can Res 2008;14:5548-5554
reduced blood flow → decreased pO2 and
nutrients availability, low pH →
ANTAGONISM:
reduced
chemotherapy
deposition, diminished cytotoxic activity
drug
Rationale for Combination Therapy
• Antivascular effects I
– inhibition of neo-angiogenesis
– induction of endothelial cell
apoptosis
– impaired mobilization of CEPs
and other bone marrow derived
cells
– vasoconstriction
de Bazelaire, C. Clin Can Res 2008;14:5548-5554
reduced blood flow → decreased pO2 and nutrients
availability, low pH →
SYNERGISM: impaired tumor cell repopulation
Rationale for Combination Therapy
• Antivascular effects II
– vascular ‘normalization’
Science 2005(307):58 – 62; Mol Can Ther 2008(7):3670-84
Rationale for Combination Therapy
• Antivascular effects III
– disruption of ‘vascular niche’ → diminished
cancer stem cell compartment
– impaired mobilization of CEPs and other bone
marrow derived cells → impaired vascular
repair → augmentation of chemotherapyrelated antivascular effects
Tumor Angiogenesis versus
Physiological Angiogenesis
Antivascular
effects
Plasma concentration
of cytotoxic drug
Conventional (MTD) Chemotherapy
Tumor cell cytotoxicity
Vascular
repair
Antivascular
effects
3 weeks
Vascular
repair
Antivascular
effects
3 weeks
Shaked et al. Cancer Cell. 2008;14(3):263-73.
Bertolini et al. Nat Rev Cancer. 2006;6(11):835-45.
Tumor cell cytotoxicity
Myelosuppression
Antiangiogenesis
Antivascular
effects
Plasma concentration
of cytotoxic drug
Metronomic Chemotherapy
3 weeks
3 weeks
Kerbel RS, Kamen BA. Nat Rev Cancer. 2004;4(6):423-36.
Emmenegger U, Kerbel RS. Onkologie. 2007;30:606-608.
VEGF Targeting Agents:
Beyond Antivascular Effects
• Direct anti-tumor effects
• Immunomodulatory effects
• Mitigation of ‘cancer-associated systemic
syndrome’
Xue et al PNAS
2008 105:18513-518
Anti-VEGF agents confer survival advantages to tumor-bearing
mice by improving cancer-associated systemic syndrome
Clinical Applications: Challenges
• phase III failures
• pancreatic cancer: Bev + Gemcitabine
• breast cancer: Bev + Capecitabine
• colorectal cancer: Vatalanib + FOLFOX (1st and 2nd line)
• diminished PFS/OS benefit in ‘2nd generation’
trials
• > 50 agent(s) in clinical development
• concurrent/sequential use?
• continuous/intermittent use?
• small molecule drugs or antibodies?
• costs
• side-effects
• course of action in case of tumor progression?
• intrinsic or acquired resistance
Mancuso et al. JCI 2006;116:2610–2621
Grothey et al. JCO 2008;26:5326-5334
Resistance to Antiangiogenic (Mono-)Therapy
Vascular
Remodeling
Evasive
Resistance
Co-option
Reduced Vascular
Dependence
Norden, Neurology 2008(70):779-787
Dissociation of antiangiogenic and
anti-tumor effects
NS: 1 week
LDM CPA: 1 week
LDM CPA: relapse
NS: 4 weeks
Emmenegger Cancer Res 66;1664-1674 (2006)
Reduced vascular dependence
Hypoxia,
Starvation
Acute survival
Proliferation
Cytostasis
• Autophagy
Cell death ~
• Necrosis
• Apoptosis
• Autophagy
dual function
‘Macro-Autophagy’
‘Stress’
Step
Initiation
Structure
Sequestration Autophagosome
formation &
maturation
Phagophore
Autophagosome
Molecules
Involved
mTOR
Beclin1 (Atg6) LC3 (Atg8)
UVRAG
Atg5
PI3kinase III Atg12
Atg9
Modifiers
mTOR
3-methyladenine
inhibitors
→ autophagy
→ autophagy inhibition
stimulation
Docking & fusion
with lysosome
Lysosome
Vesicle breakdown,
degradation of
content, release of
degradation products
Autolysosome
Cathepsins
Chloroquine
Bafilomycin A1
→ autophagy
inhibition
As a consequence of metabolic or treatment-related stress, autophagy is initiated and proceeds stepwise.
Schematic presentation of the various steps of the autophagic cascade, the structures formed, important molecules
involved and pharmacological modifiers of autophagy.
Reduced vascular dependence: a
consequence of impaired autophagy?
PC-3
standard
culture
conditions
2%
PC-3
metabolic
stress
19.47%
LCR1.1
0.43%
LCR1.1
5.26%
Promotion of tumor progression by
antiangiogenic therapy?
Accelerated metastasis after short-term treatment with
a potent inhibitor of tumor angiogenesis.
Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA,
Christensen JG, Kerbel RS. Cancer Cell. 2009 Mar
3;15(3):232-9.
Antiangiogenic therapy elicits malignant progression of
tumors to increased local invasion and distant
metastasis.
Pàez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama
H, Viñals F, Inoue M, Bergers G, Hanahan D,
Casanovas O. Cancer Cell. 2009 Mar 3;15(3):220-31.
i.v. tumor implantation
(LM2-4LUC+ Cells)
Vehicle
Group A
Group B
Group C
120 mg/kg
120 mg/kg
Days Post Tumor Implantation
Group A
1 2
Tumor Burden
(Photons/s)
10 8
3
4
5
Group B
6
7
1 2
3
4
5
Group C
6
7
1 2
3
4
5
7
10 7
21
10 6
27
-7
0
7
14
21
Days Postimplantation
30
28
35
42
6
7
Loges et al. Silencing or fueling metastasis with VEGF inhibitors:
antiangiogenesis revisited. Cancer Cell. 2009;15(3):167-70.
Conclusions I
• Antiangiogenic therapy is a clinical reality!
• Angiogenesis is a highly regulated process.
• Although the tumor vasculature is morphologically and functionally aberrant, common
regulatory mechanisms remain intact and
represent promising treatment targets.
• Antiangiogenic agents can potentiate the antitumor effects of chemotherapeutics (and vice
versa) but much remains to be learned to
optimize the clinical benefit of such combinations.
Conclusions II
• The biological understanding of the process of
tumor vascularization is rapidly evolving, but this
is not yet matched by the way antiangiogenic
agents are used in the clinic.
• There is an unmet need for biomarkers in order
to optimize dosing of antiangiogenics, and for
the selection of patients most likely to benefit
from such agents.
• Various mechanisms of intrinsic or acquired
resistance to antiangiogenic agents have been
described.
Conclusions III
• Resistance to combinations of cytotoxic and
antiangiogenic agents is less well characterized.
• Stopping the administration of antiangiogenic
agents at progression might facilitate tumor
growth acceleration.
• Novel findings suggest that antiangiogenic
therapy might promote invasive tumor growth
and metastatic disease progression.
• Tumor promoting effects could explain the yet
limited overall survival benefit resulting from the
use of antiangiogenic agents and are of special
concern in the (neo)adjuvant setting.
‘The greater our knowledge
increases, the greater our
ignorance unfolds.’
John F. Kennedy