novel antiangiogenic agents: current clinical development george w. sledge, jr. md indiana...
TRANSCRIPT
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
Downstreamsignaling pathways
Ligand sequestration: Ligand sequestration: MAbs, soluble receptorsMAbs, soluble receptors
Receptor blockingReceptor blockingMabs, soluble receptorsMabs, soluble receptors
Tyrosine kinase Tyrosine kinase inhibition: TKIsinhibition: TKIs
Inhibition of tyrosine Inhibition of tyrosine phosphorylation phosphorylation and downstreamand downstream
signalingsignalinginhibitioninhibition
p85p85
PLCPLC GRB2GRB2 SOSSOS
rasras
TranscriptionTranscriptionfactor inhibitionfactor inhibition
Inhibit receptor Inhibit receptor production; production; ribozymesribozymes
Methods of VEGF Signal Inhibition
Indirect - inhibition Indirect - inhibition of growth factors, of growth factors,
HER-2HER-2
rhuMAb VEGF (Recombinant HumanizedrhuMAb VEGF (Recombinant HumanizedMonoclonal Antibody to VEGF)Monoclonal Antibody to VEGF)
vascular endothelial growth
Humanized to avoidimmunogenicity (93%human, 7% murine).
Recognizes all isoforms of
factor, K d = 8 x 10 -10 M
Terminal half life 17-21days
Efficacy of rhuMAb VEGF
Dose (mg/kg) 3 10 20
(n=18) (n=41) (n=16)
CR 0 1 0
PR 1 3 1
Stable at 22 weeks 2 4 2
CR/PR/SD at 22 wks. 3 8 3
Rx > 1 year 0 3 -
Eligibility:- One or two prior therapies OR- Relapse within 12 months of adjuvant anthracycline and taxane- No CNS mets
RANDOMIZE
Capecitabine + rhuMAb VEGF
Capecitabine
Refractory Metastatic Disease
Accrual goal: 400 patients
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
Biochemical Cellular IC50
Receptor Ki
(M)Receptor
Phosphorylation (M)Ligand-dependentProliferation (M)
Flk-1/KDR 0.009 0.01 0.004PDGFR 0.008 0.01 0.031
c-kit ND 0.01 0.01FGFR 0.83 ND 0.70EGFR > 100 ND 8.9Flt-3 ND 0.25 0.01-0.1
SU11248 Potently Inhibits VEGFR, PDGFR and Kit in Biochemical and
Cellular Assays
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 Anti-Angiogenic 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 anti-
angiogenic 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
Eligibility:- No prior Rx for mets- Adjuvant taxane if >12 mos.Exclusion:- Her-2 +- CNS mets- Proteinuria- Uncontrolled HTN
RANDOMIZE
Arm A: Paclitaxel + rhuMAb VEGF
Arm B: Paclitaxel
E2100
Accrual goal: ~690
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
*P < 0.001 relative to Control, **P < 0.001 rel. to DC101.
0
1
2
3
4
Control DC101 C225 DC101/C225Mea
n A
scite
s Gra
de (1
thru
4)
**
**
Effect of Anti-angiogenic Therapy on Mice With Colon Cancer Carcinomatosis
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