Heralded cancer drug a nimble weapon against other diseases
Seven years ago, media reports declared that a new type of drug that starves tumors of their blood supply might soon cure cancer. The drugs were predicted to mark the beginning of the end of a disease that has terrified generations.
Of course, it didn't work out that way.
The drugs, called angiogenesis inhibitors, have become just a part of the arsenal against cancer -- not a magic bullet. But they are proving to be important, both for cancer therapy and for the treatment of other diseases that involve abnormal vessel formation.
A series of articles in last week's issue of the journal Nature highlights how scientific advances in the understanding of angiogenesis -- the formation of blood vessels -- are helping researchers learn to use these drugs more effectively.
''We are finally starting to understand the growth factors and signaling pathways that blood vessels use to make and sustain themselves," said Janet Rossant, the author of one of the Nature articles and the head of the Hospital for Sick Children Research Institute at the University of Toronto. ''Because we now understand the basic biology, we are increasingly able to take a rational approach when treating disease."
The articles in Nature emphasize that angiogenesis is a complicated but essential process that occurs throughout the body wherever organs are not receiving an adequate supply of nutrients. Even minor disturbances can lead to problems.
''There is a yin and yang to angiogenesis," Rossant said. ''In some cases, you want to stimulate it, while other times you want to block it."
Recently, cardiologists have been learning to stimulate angiogenesis in patients with blocked arteries supplying the heart in the hopes of creating new vessels to bypass these blockages. Success has been limited, but an article in last week's Nature series suggests that stimulating vessel formation may be more successful in the treatment of certain brain diseases.
''We [now] have a better understanding of the molecules and biochemical mechanisms involved in brain angiogenesis," said Dr. David Greenberg, the study's author and a professor at the Buck Institute for Age Research in California. ''Drugs that promote angiogenesis could be useful for treating diseases in which the brain's blood supply is inadequate, such as stroke . . . [as well as] in the treatment of neurodegenerative diseases" like Lou Gehrig's disease or Alzheimer's, he said.
In many other situations, however, the goal is to block angiogenesis, not promote it. Cancer is the classic example.
According to Dr. Michael O'Reilly, a radiation oncologist at the University of Texas M.D. Anderson Cancer Center in Houston, tumors secrete substances that induce blood vessels to form around them. Angiogenesis inhibitors are believed to block the formation of these vessels, limiting the tumor's nutrient supply. In contrast, conventional cancer treatments, such as chemotherapy and radiation therapy, attack the actual tumor itself.
In 2004, the Food and Drug Administration approved the first angiogenesis inhibitor -- bevacizumab, or Avastin -- for the treatment of colon cancers. Scores of other angiogenesis inhibitors are now being studied for cancer therapy.
Angiogenesis inhibitors are also being considered for a broad range of diseases other than cancer.
Several months after the approval of bevacizumab, a second angiogenesis inhibitor -- pegaptanib, or Macugen -- was approved by the FDA for the treatment of macular degeneration, an eye disease in which vessels grow behind the eye, causing loss of sight. According to the recent Nature articles, angiogenesis inhibitors not only seem to slow vision loss but may even restore it somewhat.
Another recent study in mice, published in the October issue of the journal Fertility and Sterility, looked at the use of the angiogenesis inhibitor endostatin to treat endometriosis, an often painful uterine tissue growth that can cause infertility. Researchers at Children's Hospital in Boston -- where Dr. Judah Folkman first suggested the principle behind angiogenesis inhibitors in 1970 -- found that endostatin reduced the growth of the abnormal tissue by almost 50 percent without impairing fertility.
Researchers from Children's and Brigham and Women's hospitals are also studying the role of angiogenesis in the development of atherosclerosis -- abnormal fatty deposition in artery walls that predispose people to heart attacks.
''By blocking angiogenesis at the site of these plaques, it might be possible to regulate their growth," said Dr. Karen Moulton, a cardiologist at Brigham and Women's Hospital and a researcher at Children's Hospital who has published several papers on the topic over the past few years, including an article in the November issue of the Journal of Lipid Research. At the same time, however, it will be important not to interfere with the sprouting of vessels that bypass any blockages, she said.
Despite the recent advances, the Nature articles underscore the need for further research on angiogenesis. According to Rossant, one important challenge will be to learn even more about the pathways involved so that it will be possible to more selectively block -- or promote -- angiogenesis in one part of the body without affecting other parts. This will allow for the development of new drugs with fewer side effects.
The initial media claims about angiogenesis inhibitors were premature, said Dr. Peter Carmeliet, an author of another of the Nature articles and a professor of medicine at the University of Leuven and the Flanders Interuniversity Institute of Biotechnology in Belgium. Nevertheless, he said, ''I am optimistic that we have just begun to see the therapeutic potential" of these drugs, both for cancer treatment and the treatment of other diseases.
