Cancer trials give anti-angiogenesis a boost

By Sean Henahan
The concept of treating disease by interrupting vascular growth has had a stormy ride since it was first proposed by Dr Judah Folkman. Initial enthusiasm in the 1980s gave way to despair and scepticism in the 1990s when early clinical trials failed to produce impressive results.

Now it appears the tide has once again turned in favour of Dr Folkman’s original concept. The antiangiogenic therapeutic strategy received important validation with the announcement of the first Phase III clinical trial results at annual meeting of the American Society of Clinical Oncology.

Researchers from Duke University in North Carolina reported that the experimental anti-angiogenic agent bevacizumab (Avastin, Genentech) reduced tumour size and extended survival in patients with metastatic colorectal cancer. Patients who received bevacizumab together with standard chemotherapy survived a median of five months longer than patients who received standard chemotherapy alone.

"Our study offers important proof of the philosophy that targeting a tumour’s blood supply can, in fact, inhibit the tumour’s ability to proliferate. Moreover, our current success will likely lead the cancer community to conduct large-scale clinical testing of bevacizumab as a treatment for other types of cancers," said Herbert Hurwitz, M.D., lead investigator of the study.

Bevacizumab selectively targets blood vessels within tumours, which secrete more VEGF than normal blood vessels. The drug was well tolerated with the most common side effect being moderate transient hypertension.
Following the announcement of the trial results, the US FDA granted bevacizumab fast track development status for the treatment of previously untreated first-line metastatic colorectal cancer patients.

The drug is a close cousin of rhuFab V2, an anti-VEGF compound now in advanced clinical trials in the US for treatment of age-related macular degeneration. In Phase I/II studies, the drug produced measurable improvements in vision compared to placebo treatment (see related article in this issue). A phase III study of the drug for minimally classic and occult AMD began earlier this year. Another Phase III trial for predominantly classic AMD is now enrolling patients.

Several anti-angiogenesis agents are in clinical trials for the treatment of eye disease.
These include an anti-VEGF aptamer from Eyetech, protein kinase-C antagonists from Lilly and Novartis and an integrin antagonist from Merck.

And there are more antiangiogenic agents coming down the pipeline. Researchers at Johns Hopkins' Wilmer Eye Institute and Regeneron Pharmaceuticals recently reported that a fused protein called VEGF-TRAP (R1R2) halted new blood vessel development in rodent eyes into, and stopped existing blood vessels from leaking. VEGF-TRAP contains parts of two receptors for VEGF, which, hooked together, absorb endogenous VEGF before it causes additional damage.

"Our data suggest that VEGF-TRAP deserves consideration as a potential treatment for two complications of diabetic retinopathy -- new blood vessel growth and macular oedema," "It had long-lasting effects and did not cause complications," said Hopkins researcher Peter A. Campochiaro MD.
Clinical trials to assess the medication's effects in people with diabetic retinopathy and macular oedema, and in patients with wet age-related macular degeneration are planned.

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