How well do angiogenesis inhibitors work? Biomarkers of response prove elusive.

I n 2007, the late Judah Folkman noted “a major obstacle” to the development of drugs targeted at angiogenesis, or new blood vessel growth, in tumors: the lack of noninvasive biomarkers for identifying patients most likely to respond to the drugs. Now, with three approved angiogenesis inhibitors (AIs) on the market — bevacizumab, sunitinib, and sorafenib — and hundreds of trials for others under way, the need for accurate, inexpensive, and noninvasive biomarkers has become even more pressing. “Among researchers, there is a consensus that we need to step back and better understand how angiogenesis inhibitors work, and don’t work as well as we’d hoped,” said Curzio Ruegg, M.D. , professor and head of ex perimental oncology at Switzerland’s University of Lausanne. “Better biomarkers should also help us answer the nagging question why AIs often improve progression-free survival but don’t result in better overall survival.” AI biomarkers that are detectable in blood or serum are especially intriguing because they would be relatively low cost and accessible, in contrast to the advanced imaging tools used to gauge response. And they could aid in diagnosis, staging, prognosis, and treatment selection, said Sam Gambhir, M.D., Ph.D., director of the molecular imaging program at Stanford University. For all these reasons, AI biomarker research is booming. Much of the research has focused on cytokines, including the protein targets of AI drugs, such as vascular endothelial growth factor (VEGF). But intense interest also surrounds biological markers such as circulating endothelial cells (CECs), and a subset of those cells, circulating endothelial progenitors (CEPs).