Attacking Tumors By Destroying Their Blood Vessels
At the recent meeting of the European Organization for Research and Treatment in Amsterdam, the Netherlands, the results of three promising phase I clinical trials were presented. But these were not just any phase I trials-they involved an extremely promising new compound called endostatin which destroys cancerous tumors by starving them of their blood supply.
The trials involved a total of 61 patients and 20 different types of solid tumors. They included a Dana-Farber/Partners Cancer Care trial in Boston, and two National Cancer Institute-sponsored trials performed at the M.D. Anderson Cancer Center in Houston and the University of Wisconsin Comprehensive Cancer Center in Madison.
The trials showed that endostatin is safe and well tolerated-which is the purpose of a phase I trial. "The data were remarkable in that there were no safety concerns and blood levels were very predictable," said Dr. Paul Eder of Dana-Farber. "Moreover, there were clinical responses seen even in this small trial in patients with advanced cancer."
Importantly, the results found that while endostatin cut off the blood supply to tumors, it did not interfere with the normal growth of blood vessels associated with wound healing. Phase II studies are slated to begin by March 2000.
In September 1999, nearly 1,400 cancer patients called a special phone number to sign up for the first human clinical trials of endostatin, an experimental drug that had been shown to shrink tumors in mice. Only 30 of them were selected.
Why the frenzy? Endostatin is one of a class of new anticancer agents called "angiogenesis inhibitors." Angiogenesis is the process by which new blood vessels are formed-and thus provide necessary nutrients for cancerous tumors to grow. Endostatin, and a sister protein angiostatin, work by destroying a tumor's ability to sprout new blood vessels. And laboratory tests had shown that they were fabulously effective at doing just that.
The idea of targeting a tumor's blood vessels (rather than the tumors themselves) was first introduced by Dr. Judah Folkman of Children's Hospital in Boston. He published a seminal article on the subject in the New England Journal of Medicine way back in 1971-an article that in hindsight was clearly visionary but at the time was virtually ignored.
Folkman suggested that by directly attacking the blood vessels that supply nutrients to tumors, the tumors would in effect be starved into submission, ceasing to grow and eventually dying.
Sound simple? Actually it was nothing short of revolutionary.
It took a quarter of a century, but the field of cancer research is finally taking Folkman's approach seriously-with a vengeance. There are now at least 35 anti-angiogenesis therapies being evaluated in clinical trials, and dozens more are on the immediate horizon.
Folkman labored almost alone in the field of angiogenesis inhibitors until the mid-1990s, when he was able to complete a series of successful experiments in laboratory animals that proved that endostatin could hinder blood vessel growth in cancerous tumors.
The implications of the findings were immense. But a temporary setback occurred in the fall of 1998 when scientists from the National Cancer Institute were not able to reproduce Folkman's results. However, in February 1999, a new National Cancer Institute team was finally able to duplicate his findings by actually traveling to his lab in Boston to conduct the experiments.
Since then a phenomenal amount of press has been given to endostatin and angiostatin. But there are other extremely promising angiogenesis inhibitors also working their way through clinical trials. Here are some examples.
In a phase I study conducted by researchers from the British Cancer Research Campaign, it was shown that an antivascular drug called Combrestastin A4 acted directly upon the blood vessels of cancerous tumors, thus stopping their growth. Combrestastin A4 is different from other angiogenesis inhibitors in that it acts on existing tumor blood vessels rather than preventing the growth of new ones.
A small angiogensis inhibitor called SU5416 has been found to interfere with the signals of vascular endothelial growth factor (VEGF), a compound that is crucial to blood vessel formation. Promising results have been obtained in phase III trials involving patients with non-small-cell lung cancer, Kaposi's sarcoma and colorectal cancer.
Researchers from the University of Michigan have found that the mineral copper is essential for new blood vessels to form. They have developed a novel anti-copper agent that may actually be able to fight many types of cancer because it seems to act as a "common denominator" of angiogenesis.
Researchers at Duke University in Durham, North Carolina have learned that new blood vessels form in tumors much earlier than originally anticipated. In a novel experiment, they found that new blood vessel formation begins when a tumor consists of only 60 to 80 cells, rather than hundreds or thousands of cells as commonly thought. The finding could have major significance for the timing of anticancer treatments.
Researchers at Vanderbilt University in Tennessee have identified an enzyme called COX-2 that also appears to be crucial in the formation of new blood vessels. COX-2 could similarly be a target for developing new cancer drugs that block the ability of tumors to form new blood vessels.
Recently a team of Alabama researchers was able to plant a modified herpes virus-which has been shown to stop blood vessel growth-directly into the endothelial cells which line blood vessel walls, thus causing their demise.
Ironically, even thalidomide, an agent that was banned in 1961 because of its danger to fetuses, has been found to have some potential as an anti-angiogenic agent, especially with refractory multiple myeloma.
Controlling the growth of blood vessels has been called one of the great scientific challenges of current medicine. The implications for conquering cancer are certainly profound, to say the least. But solving the mechanism of angiogenesis, or at least being able to subdue blood vessel growth in a targeted fashion, has ramifications for cardiovascular and many other diseases as well.
In the next few years, as additional angiogenesis inhibitors reach the clinical trial stage, significantly more opportunities for patients should become available. And some researchers are predicting that the first of these blood vessel destroyers may become commercially available within as little as five years, if not sooner.
SOURCES:
European Organization for Research and Treatment Symposium, November 10, 2000, Amsterdam, the Netherlands
New England Journal of Medicine, 1971; 285:1182-1186
Abstracts from the 10th European Cancer Conference, ECCO 10, Sept. 15, 1999
Journal of the National Cancer Institute, 2000; 92:143-147
Cancer Control: Journal of the Moffitt Cancer Center, 1999; 6(5): 436-458
Cancer Research, 1999; 59(8): 4574-4577
Gene Therapy, Jan. 2000; 7:43-52
Abstracts from Angiogenesis'99, Oct. 5, 1999
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