New doubts have been raised about the safety and efficacy of drugs known as angiogenesis inhibitors. These drugs are designed to block the development of new blood vessels within and around tumors. Without an effective and independent blood supply a tumor cannot grow bigger than the tip of a pencil.

This strategy for combating cancer was first put forward in the early 1970s by Judah Folkman, MD, of Harvard Medical School (Folkman 1971). Folkman believed that drugs based on his research would not only be more effective but far safer than traditional cytotoxic chemotherapy. After an initial period of intense resistance, well described in Robert Cooke's 2001 book,Dr. Folkman's War, the idea caught on big time. There are now thousands of articles on angiogenesis and cancer, hundreds of them by Folkman himself. More importantly, many of the newly approved cancer drugs are based on this concept of attacking the tumor's blood supply. But while the theory itself is elegant, and Folkman has become an icon of modern medicine, there are serious questions about how safe and effective many of the current generation of anti-angiogenic drugs are in controlling tumor growth.

A study from the University of California at Los Angeles (UCLA), published in August, 2007 in the peer-reviewed journal Cell, shows that a widely used group of anti-angiogenesis drugs is associated with serious and potentially deadly side effects. These drugs are known as VEGF inhibitors. (VEGF stands for vascular endothelial growth factor, a signaling protein that promotes the growth of new blood vessels.)

Outside In vs Inside Out

Many of the currently used VEGF inhibitors such as Avastin (bevacuzimab) work by blocking VEGF signaling from outside the cell. But the UCLA researchers are trying to understand what happens when VEGF signaling is blocked from within the cell, which is a mechanism used by some of the newer, small molecule anti-angiogenic drugs that are currently in late phase clinical trials. According to a UCLA press release, "the result was unexpected, and sobering." More than half of the mice in the study suffered heart attacks and fatal strokes. The mice that remained alive developed serious systemic vascular disease, according to Luisa Iruela-Arispe, a professor of molecular, cell and developmental biology and director of the Cancer Cell Biology program at UCLA's Jonsson Cancer Center (Lee 2007).

"This was an extremely surprising result," said Iruela-Arispe, who is past president of the North American Vascular Biology Organization and a national expert on angiogenesis. "I think this study is cause for some caution in the use of angiogenesis inhibitors in patients for very long periods of time and in particular for use of those inhibitors that block VEGF signaling from inside the cell."

It is already known that 5 percent of patients taking Avastin develop blood clot-related side effects. But because Avastin was approved only three years ago, it is unclear what adverse effects may occur when patients remain on the drug for many years, according to Iruela-Arispe.

In her three-year study, Iruela-Arispe created mice that were missing VEGF in the endothelial cells that line the inside of blood vessels and form the interface between circulating blood and the vessel wall. The UCLA team did not expect to see much of an effect because the amount of VEGF that is created inside endothelial cells is tiny compared to the amount created outside the same cells. But they soon had a bombshell finding: 55 percent of the mice died by 25 weeks of age, which is the equivalent of age 30 in humans. The remaining mice lived on, but were all very ill for the remainder of their lives.

"Some side effects have already been identified in people taking angiogenesis inhibitors," said Iruela-Arispe. "And they've been along the lines of what we're seeing in the lab."

Oddly, even high levels of VEGF outside the cells did not compensate for the absence of very tiny amounts within the cells. The missing internal VEGF had "a tremendous biological significance," Iruela-Arispe said. "Clearly there is signaling from inside the cell that is different from signaling initiated outside the cell," she added. "When there is no VEGF signaling inside the cell, the endothelial cells die. The intracellular part of the VEGF signaling loop is required for cell survival. This is the first demonstration that intracellular signaling is an important event."

To be concluded, with references, next week.

--Ralph W. Moss, Ph.D.

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