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Therapies directed at vascular endothelial growth factor
Paul W Manley1, Georg Martiny-Baron, Jean-Marc Schlaeppi
1Novartis Pharma Ltd, CH-4057 Basel, Switzerland.
Expert Opinion on Investigational Drugs
|November 30, 2002
Summary
Targeting vascular endothelial growth factor (VEGF) receptors inhibits tumor angiogenesis. Small-molecule inhibitors show promise for chronic therapy, but combination strategies require caution due to adverse events.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Angiogenesis inhibition via vascular endothelial growth factor (VEGF) receptor targeting offers tumor selectivity.
- Neutralizing antibodies, soluble receptors, and ribozymes provide high selectivity, minimizing off-target side effects.
- Small-molecule, orally-active protein kinase inhibitors are attractive for chronic therapy, but kinase specificity is challenging.
Purpose of the Study:
- To review the therapeutic potential of VEGF receptor inhibitors in cancer treatment.
- To evaluate the challenges and clinical progress of small-molecule kinase inhibitors targeting VEGF receptors.
- To discuss the role of VEGF pathway blockers in combination therapies and associated risks.
Main Methods:
- Review of current literature on VEGF receptor inhibitors.
- Analysis of clinical trial data for specific kinase inhibitors (PTK787/ZK222584, ZD6474).
- Evaluation of combination therapy strategies involving anti-VEGF agents and other treatments.
Main Results:
- Several synthetic VEGF receptor kinase inhibitors have shown promising clinical data.
- PTK787/ZK222584 and ZD6474 are advancing into large-scale clinical trials.
- VEGF pathway blockers are likely best used as adjuncts rather than monotherapy.
Conclusions:
- VEGF receptor inhibitors represent a promising anti-angiogenic strategy in oncology.
- Combination therapies require careful consideration due to potential bleeding and thrombotic adverse events with certain agents.
- Further research into targeted kinase inhibition and combination strategies is warranted.