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This report originally appeard on the Sapient Health Network web site, which later became WebMD.

Angiostatin and Endostatin in Good Company with Slew of Promising Cancer Drugs 

Exclusive Report from the 1998 ASCO Meeting
By Andrew Holtz 

June 9, 1998 -- 

While a flurry of media attention recently focused on a pair of new drugs, angiostatin and endostatin, that eliminated tumors in laboratory mice, other researchers have been quietly moving forward with trials of similar agents in people with cancer. 

Dr. James Pluda of the National Cancer Institute says, "There are a dozen or more of these compounds currently in clinical trials around the country. So people in fact can get these drugs, can receive this kind of therapy, and we should get the word out that this is going on, and not focus so much on compounds that so far have been given only to mice and are at least a year away from the clinic." 

The results of two early trials presented at the American Society of Clinical Oncology annual meeting show these "anti-angiogenesis" drugs can be used safely, and may be able to slow or even stop tumor growth in some patients. 

The theory behind all of these drugs was put forward more than a quarter-century ago by Dr. Judah Folkman at Children's Hospital in Boston. He observed that tumors send out chemical signals that trigger new blood vessels to grow and nourish the tumors, a process called angiogenesis. He argued that if the blood vessel growth could be blocked, tumors would starve. One researcher compares it to a new building development that needs roads. Block the bulldozers from clearing the land, or asphalt crews from paving the street, and the development will wither. 

Though the concept of anti-angiogenesis has been around for decades, it is only in recent years that scientists began identifying the specific chemical signals involved in triggering blood vessel growth. 

One of those signals is called Vascular Endothelial Growth Factor, or VEGF. Researchers at Indiana University, City of Hope Medical Center in Los Angeles, and M.D. Anderson Cancer Center in Houston gave 25 patients with metastatic cancer an antibody, called anti-VEGF, designed to attack the VEGF protein. Researchers say anti-VEGF was well-tolerated. Three patients suffered tumor bleeding, including one stroke, though the researchers say there is no evidence the treatment was to blame. 

Dr. Michael Gordon of Indiana University says the results justify moving to the next phase of studies, that will begin to test anti-VEGF's effectiveness. "The patients that were treated on this study had a variety of diseases, including sarcomas, kidney cancer, breast cancer, head and neck cancer, and so it does not constitute a set group of patients to evaluate the efficacy of the drug," he says. "Nonetheless, we did see one minor response in one patient treated at the highest does level. That patient was subsequently followed, and gradually over time, as one would predict, his disease began to re-grow. And he is being re-treated with the drug, but it is as yet too early to define whether or not he will be responding again." 

Drugs like anti-VEGF may be able to do more than just prevent new blood vessels from growing to supply tumors. They may also be able to attack blood vessels that are already feeding the cancer. "Since it has been hypothesized that many of these factors also act as survival factors for growing blood vessels, by disrupting them one could lead to the death of growing blood vessels," says Dr. Gordon. "And so not only would you prevent new blood vessels, you might kill rapidly growing blood vessels, such as those that are frequently seen in tumors." 

A second anti-angiogenesis agent that has now been through the first phase of human testing is called TNP-470. It's a synthetic form of a chemical secreted by aspergillus fumigatus mold. Researchers discovered the chemical by accident, when mold contaminated a laboratory cell culture and inhibited blood vessel growth. 

Researchers gave TNP-470 to 33 patients with metastatic kidney cancer, which usually resists standard treatment. In two patients the researchers saw some signs of response. In 5 of 20 patients followed for more than 16 weeks, the tumors did not grow or spread. 

Dr. Nicholas Vogelzang, of the University of Chicago, says, "We conclude that TNP-470 is well-tolerated over long periods of time, but that tumors do not shrink. Optimistically the four patients who continue to receive the drug may be having benefit from it. Pessimistically speaking, these four patients may just have very slowly growing kidney cancer." 

If further studies show TNP-470 can indeed stop some tumors from growing, it may offer a way to keep cancers under control. "If the tumor doesn't grow, you can live a normal life," says Dr. Vogelzang. "It's the growth of the tumor that's the problem. So the sheer presence of the tumor, if it's subclinical, or before causing clinical symptoms, is not necessarily life-threatening. So a static agent, an agent that would prohibit or inhibit the growth, is still a very clinically relevant end-point, especially a drug that has no side effects." 

NCI's Dr. Pluda agrees, "Stasis can be a positive clinical finding. If we can convert cancer into a chronic disease, whereby patients can live for 30 years in a symbiotic relationship with their tumor, where their tumor doesn't bother them and the drugs keep the tumor in check, I'm willing to accept that as an oncologist, in the absence of being able to actually cure somebody. We treat diabetics, we don't cure diabetes at this point." 

The researchers say it is hard to make direct comparisons between the anti-angiogenesis agents they tested in people, and the two drugs, angiostatin and endostatin, being studied in Dr. Folkman's laboratory animals. However, Dr. Vogelzang says when TNP-470 was tested in mice, it did not produce results as dramatic as those recently seen with angiostatin and endostatin. He says that is not surprising, since TNP-470 is an earlier-generation drug. 

Yet Dr. Pluda stresses the importance of the results of trials in people with cancers, even if they have not produced the kind of quick cures seen in controlled pre-clinical laboratory tests. "Pre-clinical is all it is, and not getting about, 'Wow, this is going to cure cancer;' because I know that lots of things have induced people to go, 'Wow, this is really exciting, and terrific and awesome,' and yet did not translate into clinical benefit." 

Dr. Pluda points out that many treatments, including the interleukin drugs and interferon, appeared marvelously effective in pre-clinical trials; however, when actual cancer patients began taking the drugs, the results were not as spectacular, and the side-effects appeared more formidable. 

The researchers also caution against putting too much emphasis on individual drugs, or even single approaches. They say anti-angiogenesis agents are unlikely to be able to cure cancers alone, that they will likely be used in combination with other treatments, in order to attack tumors along multiple fronts simultaneously. 

In the same way, taking two or more anti-angiogenesis agents together may offer advantages. Dr. Gordon says, "Combinations of anti-angiogenic agents, attacking this process in mechanisms that differ slightly, similar to the way we developed combination chemotherapy, may actually hold more potential than any one, single agent down the road." 

Source: Exclusive SHN Report 

Copyright 1998 by Sapient Health Network. All rights reserved. 

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