Novel Antiangiogenic Agents:
Current Clinical Development
George W. Sledge, Jr. MD
Indiana University Cancer Center
Antiangiogenic Therapies:
Potential Targets
• Block pro-angiogenic molecules (e.g.,
VEGF)
• Add anti-angiogenic regulators (e.g.
angiostatin, endostatin, TSP-1)
• Inhibit stroma-degrading enzymes (e.g.,
MMPIs)
• Target vascular antigens (e.g., avb3
integrin)
• Attack pericytes
VEGF Is a Key Mediator of Angiogenesis
Upstream activators
of VEGF synthesis
Downstream
signaling pathways
Methods of VEGF Signal Inhibition
Ligand sequestration:
MAbs, soluble receptors
Indirect - inhibition
of growth factors,
HER-2
Receptor blocking
Mabs, soluble receptors
p85
ras
GRB2
PLCg
Inhibit receptor
production;
ribozymes
Tyrosine kinase
inhibition: TKIs
SOS
Inhibition of tyrosine
phosphorylation
and downstream
signaling
inhibition
Transcription
factor inhibition
rhuMAb VEGF (Recombinant Humanized
Monoclonal Antibody to VEGF)
 Humanized to avoid
immunogenicity (93%
human, 7% murine).
 Recognizes all isoforms of
vascular endothelial growth
factor, Kd= 8 x 10-10M
 Terminal half life 17-21
days
Efficacy of rhuMAb VEGF
Dose (mg/kg)
3
10
(n=18) (n=41)
CR
0
1
PR
1
3
Stable at 22 weeks
2
4
CR/PR/SD at 22 wks. 3
8
Rx > 1 year
0
3
20
(n=16)
0
1
2
3
-
Refractory Metastatic Disease
Eligibility:
- One or two prior therapies
OR
- Relapse within 12 months of
adjuvant anthracycline and
taxane
- No CNS mets
R
A
N
D
O
M
I
Z
E
Accrual goal: 400 patients
Capecitabine + rhuMAb VEGF
Capecitabine
Toxicities of Anti-VEGF Therapy
•
•
•
•
•
Hemorrhage (lung cancers)
Hypertension (anti-VPF)
Headaches/migraines
Clots (maybe)
Proteinura/nephrotic syndrome
Intracellular Signaling Pathways Activated by
VEGF Binding to VEGFR2
ZD6474
SU11248 Potently Inhibits VEGFR,
PDGFR and Kit in Biochemical and
Cellular Assays
Receptor
Biochemical
Ki
(M)
Flk-1/KDR
PDGFR
c-kit
FGFR
EGFR
Flt-3
0.009
0.008
ND
0.83
> 100
ND
Cellular IC50
Receptor
Ligand-dependent
Phosphorylation (M)
Proliferation (M)
0.01
0.01
0.01
ND
ND
0.25
0.004
0.031
0.01
0.70
8.9
0.01-0.1
Anti-Flt-1 Ribozyme
Uppercase = ribonucleotides; lowercase = 2’-O-methyl ribonucleotide; B = inverted 2’-deoxyribose
abasics; s = phosphorothiolate linkage; u4 = 2’-C-allyl nucleotide.
Sandberg JA et al. J Clin Pharmacol. 2000;40:1462-1469.
The Problem With AntiAngiogenic Therapy:
Resistance
Mechanisms of Resistance
•
•
•
•
•
•
•
Endothelial cell heterogeneity
Tumor heterogeneity
Impact of tumor microenvironment
Compensatory response to hypoxic insults
Re-growth independence from angiogenesis
Vascular mimicry
Vasculogenesis
Thwarting Resistance
• Use chemotherapy with anti-angiogenic
intent - ‘metronomic therapy’
• Combine with chemotherapy
• Combine multiple anti-angiogenics
• Combine with other biologics
• Use anti-angiogenics as targeted therapy
• Use anti-angiogenics in adjuvant setting
Use Standard Therapies With
Anti-Angiogenic Intent
• Concept:
– Standard chemotherapeutic agents have
potent anti-angiogenic activity
– We use them poorly from an antiangiogenic standpoint
– Metronomic therapy (chronic low-dose
chemotherapy) overcomes resistance
Metronomic Therapy in the
Clinic: Colleoni
• Study design: Phase II trial of CTX 50 mg
p.o. qd + MTX 2.5 mg p.o. D 1,2 qwk.
• Patient Characteristics: 64 MBC pts, 32
with 1 prior regimen, 20 with 2+ prior
regimens, 41 with adjuvant regimen
• Results: CR + PR = 19%; CR + PR + SD
>24 wk = 31.7
Combine anti-angiogenic agents
with standard chemotherapy
• Concept:
– Chemotherapeutics are anti-angiogenics
– Pro-angiogenic factors protect tumor
endothelium
– Preclinical support for combinations of
anti-angiogenics’s with CT
E2100
Eligibility:
- No prior Rx for mets
- Adjuvant taxane if >12 mos.
Exclusion:
- Her-2 +
- CNS mets
- Proteinuria
- Uncontrolled HTN
Accrual goal: ~690
R
A
N
D
O
M
I
Z
E
Arm A: Paclitaxel + rhuMAb VEGF
Arm B: Paclitaxel
Combine anti-angiogenic agents
with each other
• Concept:
– Angiogenesis is a redundant process
– Tumor progression is associated with
angiogenic growth factor progression-->
resistance to individual agents
– Preclinical evidence of combinatorial
benefit with anti-angiogenics
Combine anti-angiogenic agents
with other biologics
• Concept:
– Angiogenesis is under control of
numerous polypeptide growth factors
– Targeting growth factor receptors
decreases angiogenesis
– Potential for additivity/synergy
Mean Ascites Grade (1 thru 4)
Effect of Anti-angiogenic Therapy on
Mice With Colon Cancer Carcinomatosis
4
3
2
*
1
*
**
0
Control
DC101
C225
DC101/C225
*P < 0.001 relative to Control, **P < 0.001 rel. to DC1
Use anti-angiogenic therapy as
targeted therapy
• Concept:
– Antiangiogenic therapy is viewed as
general therapy
– Resistance to specific agents implies
specific resistance phenotypes/genotypes
– Target therapy to specific tumors
Use anti-angiogenic therapy as
adjuvant therapy
• Concept:
– Anti-angiogenic therapy has not eliminated
drug resistance
– Pro-angiogenic factors increase as tumors
progress
– Resistance is a function of tumor
size/mutation rate
– Treat tumors before they become resistant
Adjuvant Angiogenesis:
Requirements
•
•
•
•
•
•
Chronic safety
Combinatorial safety
Chronic dose maintenance
Large Proof-of-Concept trials
Disease-specific rationale
Proof of efficacy in advanced disease
(???)
BMS-275291
• Potent, peptidomimetic inhibitor of MMPs
– rationally designed to spare sheddases
• metalloproteinases which process TNF-a, TNF-aRII
• Daily, oral, outpatient regimen
• Expectations
– No dose-limiting arthritis
– Complementary efficacy to chemotherapy
BMS-275291 Adjuvant Pilot
Patients with Stage I-IIIa breast cancer
receiving standard therapies randomized (2:1)
to:
• BMS-275291 1200 mg/day x 12 months
• Placebo daily x 12 months
• All patients may continue open-label for one
additional year; Accrual goal = 120