At a joint session of the American Society of Hematology and the American Society of Clinical Oncology, held at the ASH annual meeting in early December, Lee Ellis, professor in the departments of surgery and cancer biology at the University of Texas MD Anderson Health Sciences Center in Houston, noted that "when we discuss proven anti-angiogenic therapy, we're really only discussing anti-VEGF."

The currently available anti-angiogenesis drugs - Avastin (bevacizumab), from South San Francisco-based Genentech Inc. and Erbitux (cetuximab), from New York's ImClone Systems Inc., target the vascular endothelial growth factor or its interaction with its receptor.

But if preclinical research reported in the Dec. 21, 2006, issue of Nature pans out, VEGF's clinical monopoly may come to an end. Researchers from Genentech and Tarrytown, N.Y.'s Regeneron Pharmaceuticals Inc. published back-to-back papers on a new angiogenesis target, Delta-like ligand 4 or Dll-4.

Dll-4, which binds to notch receptors, is required for blood vessel development, strongly expressed in tumor vasculature and induced by VEGF-signaling - three good reasons to test blockers of the compound for their anti-angiogenic effect in cell culture as studied by Genentech, and in tumor xenografts in the case of Regeneron's studies.

The results of those early studies were hardly auspicious for an angiogenesis blocker. Blocking Dll4 did reduce notch signaling but led to significantly increased blood vessel density in both Genentech's in vitro studies and Regeneron's xenografts.

But "we always like to confirm and extend the in vitro studies," Minhong Yan, scientist in Genentech's department of tumor biology and angiogenesis and senior author of their paper, told BioWorld Today. It paid off in this case. There was plenty of vasculature after blocking Dll-4, but it was nonfunctional.

Indeed, from the point of view of the tumors, it was counterproductive: "Contrary to conventional wisdom, the extra blood vessels formed through the blockade of Dll-4 served to choke the tumors rather than feed them," said Gavin Thurston, Regeneron's director of oncology and angiogenesis and senior author of the paper.

Consequently, inhibiting Dll-4 signaling led to the inhibition of tumor growth in a variety of tumor types, including those that were resistant to the blockade of VEGF.

Genentech's Yan called the findings on tumor growth a "delightful surprise" given the effects on vasculature. The vasculature results "would not naturally allow you to predict the outcome" of the studies on tumor growth, he acknowledged.

The Genentech group used a monoclonal antibody for its studies, though the company's clinical plans for it, if there are any, have not been disclosed publicly. Regeneron announced that it plans to develop a fully human monoclonal antibody to Dll-4 that was produced using the company's VelocImmune technology, though in the work reported in Nature, the company's scientists used purified recombinant soluble Dll-4 protein and polyclonal antibodies for their studies.

In the Dec. 22, 2006, issue of Science, Avastin also received the equivalent of an honorable mention in the top 10 breakthroughs of 2006 as a drug that could help those suffering from wet age-related macular degeneration, which is caused by abnormal retinal blood vessel growth.

The company's Lucentis (ranibizumab), which was approved for use in wet AMD in 2006, was named as the breakthrough of the year; but Science's editorial staff noted that researchers also are looking at bevacizumab as a possible treatment. If it works, it "could be a cheaper alternative to ranibizumab, which costs $1,950 per monthly dose."

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