VEGF antagonists

Abstract

The majority of cancer have an absolute requirement for angiogenesis, the process by which new blood vessels are formed. The most potent angiogenic cytokine is vascular endothelial growth factor (VEGF) and there has been substantial research into the development of VEGF/VEGF receptor (VEGFR) antagonists. To date these strategies have included gene therapy techniques that deliver antisense oligonucleotides, soluble VEGFRs that function in a dominant negative fashion and ribozymes. Additional strategies have included the development of receptor tyrosine kinase (RTK) inhibitors and monoclonal antibodies (mAbs) directed against VEGF or the signalling receptor. The most promising agents appear to be the monoclonal anti-VEGF antibodies and the RTK inhibitors as these have demonstrated broad spectrum antitumour activity in vivo and single agent activity in early phase clinical trials in patients with advanced pre-treated breast and colorectal carcinoma and Kaposi's sarcoma. The RTK inhibitors are of particular interest as they can be administered by mouth. Collation of the early clinical trial data suggests that VEGF antagonists are largely well-tolerated but may be associated with vascular toxicities such as haemorrhage and thromboembolic events. Combination studies of chemotherapy and VEGF antagonists are underway but the benefit of these regimens will need to be established in adequately powered Phase III studies. Potentially these agents may play a role in the treatment of both early (adjuvant) and advanced cancer. The efficacy of the drugs will be explored in a number of non-malignant conditions including rheumatoid arthritis (RA), psoriasis, diabetic retinopathy and possibly as non-steroidal contraceptives but the overall clinical development of these agents can only be optimised if appropriate biological end points are identified and incorporated into clinical trials.