What You Should Do If You Have Cancer

A new cancer drug will enter human clinical trials in the United States before the end of this year. The scientific literature shows that this drug induces a consistent and significant reduction in tumor growth in laboratory animals. In many cases the primary and metastatic cancer lesions are put into a dormant state and no longer propagate.

The evidence, published in the world's most prestigious scientific journals, indicates that this may be the most promising cancer treatment ever discovered. The therapy is non-toxic and has shown efficacy against every type of cancer it has been tested against. One study showed that it suppressed metastatic tumor growth rates by 90%. Another study showed primary tumors regressing to become "dormant microscopic lesions."

For cancer victims given less than two years to live, getting into these clinical trials could be a matter of life or death. Before raising any premature hope, we want to state that this anti-cancer therapy consists of two drugs, endostatin and angiostatin. The FDA, however, is only permitting one of these two drugs (endostatin) to be used in the initial clinical trials. In other words, the FDA is not allowing terminally ill humans to use the two drugs that worked so remarkably well together in the animal studies. There is still reason to believe, however, that just one-half of this drug combination (the endostatin) could save the lives of human cancer victims who have been given little or no hope by the medical establishment.

The Life Extension Foundation is encouraging those suffering from a non-treatable form of cancer to consider entering the first clinical trials in which endostatin, a potent angiogenesis-inhibiting drug, will be tested for the first time in humans.

Primary and metastatic tumors require ongoing angiogenesis (new blood vessel formation) to support their growth. This is an undisputed fact based on today's understanding of oncological processes. Weak angiogenesis-inhibiting agents such as shark cartilage have not shown adequate efficacy. Angiostatin and endostatin are naturally produced proteins that shut off new blood vessel formation to tumors.

Angiostatin and/or endostatin have produced dramatic remissions in animal studies. Human cancer patients will soon gain access to endostatin in FDA-sanctioned human clinical trials. For an inside report about endostatin and how you can apply to be part of the first human clinical studies, read on.

Scientists Test New Cancer Drug in Humans

Endostatin, a natural protein, may hold the key to wiping out a ruthless killer. Before year's end, scientists are slated to begin human tests of a new, natural cancer drug that brought about miraculous cures in mice.

The drug endostatin is derived from a protein found in the human body. In animal trials, the protein drug wiped out several forms of cancer by choking off the blood supply to tumors.

Although many cancer patients develop a resistance to conventional drugs, they aren't likely to do so with endostatin. What's more, the new natural treatment appears to stop cancer from spreading to other parts of the body.

"It's a breakthrough," says Dr. Robert Kerbel, a University of Toronto professor of medical biophysics. "Here, for the first time, may be a way of getting around drug resistance, which seemed an invincible and inevitable property of malignant tumors."

So far, endostatin has worked only in mice. Now the National Cancer Institute in Frederick, Md., wants to find out if the drug can starve human tumors. At press time, clinical trials were being prepped to begin at the University of Texas, M.D. Anderson Cancer Institute in Houston, the University of Wisconsin's Comprehensive Cancer Center in Madison, and the Dana Farber Cancer Institute in Boston. If endostatin helps human cancer patients, Kerbel says, the drug "could herald a new era of cancer treatment." Thus, says Dr. Richard Klausner, NCI director, "We are putting nothing on higher priority than getting [endostatin] into clinical trials."

Cancer and angiogenesis

Cancer long has baffled medical science. The debilitating, frequently fatal disease often spreads throughout the body at an alarming rate. Until recently, scientists did not fully understand why.

Dr. Judah Folkman, a professor of surgery at Children's Hospital in Boston, an affiliate of Harvard Medical School, has spent the last 30 years championing a controversial theory. In 1971-around the time that President Nixon declared "war" on cancer-Folkman theorized that the disease develops through a process called angiogenesis.

Almost every tissue in the body derives blood from hair-thin capillaries that lace our tissues. Through capillaries, nutrients, oxygen and various signaling molecules diffuse into cells.

Tumors start out without circulation. In early stages, they are limited to a trickle of nutrients that can diffuse from the nearest capillary. Then, somehow, tumors begin to stimulate healthy tissue to make thousands of new blood vessels to supply the cancerous growth. Without this ability to nourish itself and grow, a tumor cannot enlarge.

At the same time, a primary tumor also sends chemical signals that prevent other tumors from growing in other parts of the body. When the tumor is removed, there is nothing to stop other tumors from growing elsewhere. That's why some people become ridden with cancer after undergoing tumor removal.

Like Dr. Kilmer McCully, whose theory linking heart disease and homocysteine was ridiculed until science later proved him right, Folkman suffered the scorn of his peers as he attempted to isolate the faint chemical growth signals he believed that tumors sent out.

Now advanced biomedical technology has pinpointed those signals, and most scientists accept that angiogenesis underlies cancerous tumors. In recent years several drugs, including interferons, steroids and certain hormonal agents, have been developed to stop or slow angiogenesis. In fact, at least 11 anti-angiogenic drugs are in clinical trials now, and three have proved effective enough to make it to final phase.

Some of the drugs, such as endostatin, are derived from proteins, others are based on smaller molecules. Ironically, one promising drug on trial now is thalidomide, which once was sold as a sedative and caused notorious birth defects in the children of women who took it.

Another drug, 2-methoxyestradiol (2-ME), is a natural estrogen metabolite believed to be an inhibitor of angiogenesis and also an anti-tumor agent. Dr. Robert D'Amato and colleagues at Children's Hospital discovered in preclinical studies that 2-ME inhibited the growth of breast cancer cells and stopped tumors from sprouting new blood vessels.

In addition, the NCI is investigating a drug called Col-3, and negotiating with several biotechnology companies to examine other anticancer compounds. But of all the anti-angiogenic drugs, endostatin and angiostatin appear to hold the greatest potential for saving lives.

Breakthrough discoveries

Angiostatin and endostatin drugs were discovered by Dr. Michael O'Reilly, a research fellow at Children's Hospital who has worked closely with Folkman. O'Reilly discovered angiostatin first. The cancer-preventing chemical turned up in the urine of mice afflicted by large tumors. Angiostatin, O'Reilly later determined, is used by the human body as part of a blood-clotting mechanism. Endostatin appears to be produced by tumors to stop other tumors from developing throughout the body.

O'Reilly and Folkman found that the drugs could eradicate several forms of cancer in mice by starving tumors of nutrient-rich blood. In fact, the drugs were so powerful that they shriveled tumors in mice that would weigh several pounds in a human being. But unlike some anticancer drugs, endostatin and angiostatin do not harm normal cells. In addition, the new drugs suppress metastasis, the process by which tumor cells spread to other sites in the body.

Folkman called the protein combination "very promising" when he announced the discovery in May of 1998. But, he added, "We have to be careful with expectations. You always have the risk that something will fail. But if [the drugs] work in patients as well as they work in laboratories-and that's a big if-then one might hope that they improve our ability to treat cancer."

How the drugs work

Folkman and other scientists are excited about the new drugs because cancer is a difficult disease to treat with existing medicines.

"Tumor cells can do things with their genes that are amazing," Kerbel explains. "They can shuffle their genetic information. They can amplify certain genes. They can turn off some genes, and mutate others." Because "you're dealing with a moving target," he adds, "cancer can be hard to hit with a killing drug."

In addition, conventional cancer therapies often cause severe side effects. That's because the drugs slow cell division, particularly in the gut and bone marrow, where cells divide rapidly. Angiostatin and endostatin, however, slow cell growth only in blood vessels and the heart, where cells divide much less frequently. Thus, the new drugs don't appear to cause side effects, such as the nausea often produced by chemotherapy. But they could cause bleeding and difficulty with wound healing, two potential problems doctors will be monitoring closely.

Another problem with existing cancer drugs is that they sometimes stop working after patients develop a resistance to them. Of the more than 500,000 annual deaths from cancer in the United States, many follow the development of resistance to chemotherapy.

Drugs that work at first lose effectiveness over time because cancer cells divide rapidly and sloppily, forming thousands of mutant cells. If any of these mutant cells resist the anticancer drugs, they divide and form a drug-resistant line of cancer cells.

That's what happened after Folkman and O'Reilly gave a conventional anticancer drug to mice with aggressive lung cancer. The drug controlled the tumors for 13 days. But the mice soon developed a resistance to the drug, and the tumors resumed growing.

To find out whether tumors would develop resistance to angiostatin and endostatin, researchers gave the new drugs to mice in an on-off cycle. In other words, they attempted to stimulate any drug resistance the mice might develop for the new medicines.

Remarkably, there was no resistance, no matter how many times the scientists gave the drugs to the mice. Every time the mice received the blood-vessel inhibitors, their tumors shrank as rapidly as they had the first time they were exposed to the drugs.

As Folkman put it: "This is the first time one has been able to repeatedly treat tumors in animals and not have the tumors develop resistance against the drugs."

What accounts for the lack of resistance to the new drugs? Angiogenesis occurs when genetically stable endothelial cells in blood vessels divide to build new blood vessels. It is those cells that the inhibitor drugs affect.

"The tumor cells could mutate and develop resistance, but it will be more difficult for the endothelial cells to do so," explains James Mixson, a research assistant professor at the University of Maryland School of Medicine who also studies angiogenesis in mice.

Endostatin and angiostatin "are not directed at the actual tumor cell, but rather at the blood vessels that feed it," says Dr. John W. Holaday, chairman, president and chief executive officer of EntreMed, a small biotech company in Rockville, Md., that produces endostatin. Thus, Holaday, says, the drugs retain their tumor-shrinking abilities.

Even more important, Folkman says, is the fact that the new drugs appear to keep on working, even after therapy is discontinued. After mice stopped taking the drugs, for example, tumors remained dormant for up to 165 days. That's the human equivalent of 16 years.

"All endostatin-treated mice remained healthy and gained weight normally," Folkman recalls.

How is it that tumors remain dormant after the drug therapy is stopped? Perhaps, researchers speculate, the drugs leave a residual "capsule" of angiogenesis inhibitor around the tumor. Or, they may initiate a sort of programmed cell death in tumors.

Tests in mice

In trials with mice, endostatin and angiostatin worked remarkably well against cancers in the colon, prostate, breast and brain.

Twenty mice had large cancerous growths, which researchers removed. Ten mice were given salt water and 10 were given angiostatin. There was no recurrence of cancer in any of the 10 mice treated with angiostatin. But all of the water-treated mice developed new cancers.

Endostatin was given to mice in cycles. Small amounts of the protein caused tumors to shrink until they were barely visible. Treatment then was stopped and did not begin again until tumors had grown to more than 1 percent of body size in the mice. Miraculously, endostatin not only shrank the tumors, but caused them to become dormant, so they remained inactive even after the treatment ended.

Problems with replication

But scientists from the NCI were unable to reproduce Folkman's results. Folkman attributed the failure to technical problems, including possible trouble in transporting the fragile proteins, or improperly injecting them in the mice.

"There are often many problems that have to be overcome in transferring a new technique from one lab to another," Folkman explained, adding that it usually takes at least two years for other scientists to repeat an experiment and publish results.

Eventually other scientific teams, including one from the NCI, succeeded in independently testing endostatin and angiostatin. And the NCI's Klausner lost no time in heralding the discovery. "These two new drugs, which block the tumor blood vessels, are incredibly effective at preventing the growth of cancers in mice, even those with large tumors," he announced.

"We look forward to working closely with the NCI," says EntreMed's Holaday. "The collaborative efforts will provide an efficient means for expediting the development of these potential cancer drug candidates."

Human trials

But several steps had to be taken before human trials could begin. First, scientists had to figure out a way to get adequate supplies of endostatin for preclinical and initial human clinical trials. So far it has been difficult to produce the large quantities needed for human tests. To overcome the problem, the NCI is working closely with EntreMed. Researchers are developing bacterial, mammalian-cell or yeast "factories" that produce the proteins.

Scientists also must ensure that drugs produced for the trials were free of any impurities that might cause side effects in people. In recent months, researchers have developed a drug-production process that ensures purity.

And, as part of the preclinical development process, researchers must perform necessary toxicologic and pharmacologic studies of the new drug. Scientists have been developing tests to check the drug's action on body chemistry and organ systems. Required safety testing will follow.

Although endostatin and angiostatin have been used in combination to treat mice, the human trials will involve only endostatin. Presumably, angiostatin will be tested later in humans.

During the first phase of the endostatin trials, scientists will test for adverse side effects and also look for signs that the drug is halting growth of tumors, says Dr. James Pluda, NCI senior drug investigator. If the drug is found to be safe, it will be tested for effectiveness.

The first phase begins with 25 patients at Dana Farber Cancer Institute, Brigham and Women's Hospital and Massachusetts General Hospital in Boston. Candidates will have tumors caused by lymphoma or cancers of the colon, breast and other organs.

Then similar phase-one tests will begin after the Boston trials. These will be done at the University of Texas, M.D. Anderson Cancer Institute in Houston and the University of Wisconsin's Comprehensive Cancer Center in Madison. Both sites will conduct trials on 15 to 25 patients with solid tumors caused by lung cancer, lymphoma, breast cancer, colon cancer and prostate cancer.

Some concerns

NCI investigators hope that the new drugs will work in humans as well as they have worked in mice. But there are several variables to consider:

• So far, scientists have been treating tumors that were transplanted in mice. The biology of transplanted tumors is different from that of naturally occurring tumors. Often transplanted tumors are not accurate predictors of what will happen with natural human cancers.

• Laboratory animals, such as mice, don't metabolize drugs the same way that humans do. This can affect the success of treatments with proteins.
• Because humans are much larger than mice, they will require much larger quantities of the drug. Scientists don't know what effect large amounts of endostatin might have on humans.
• Other anti-angiogenesis drugs have shown promise in the laboratory and then performed poorly in human tests. Interleukin-2, for example, was very successful in treating tumors in mice. But subsequent studies in people showed that it caused significant side effects, such as a severe drop in blood pressure and leaking of fluid from blood vessels.

What the future holds

Human trials of endostatin will enable researchers to learn much more than they now know about cancer and how it kills. In fact, scientists may be able to learn more about every stage of cancer development. And that knowledge could help them to devise more innovative treatments.

If the new drug works in humans, it eventually will become available for consumption by patients. Medications in late-phase clinical trials may be approved by the U.S. Food and Drug Administration for general use as cancer treatments within two to five years. Some anti-angiogenesis drugs already are at that stage. These include marimastat, a matric metalloproteinase inhibitor, and thalidomide, a drug with multiple mechanisms that has shown some evidence of biologic activity in gliomas (brain tumors) and Kaposi's sarcoma.

If all goes well, endostatin may become available early in the next century. But some patients may be able to get it sooner. The FDA sometimes approves "compassionate use" for promising drugs that have not been fully approved. The compassionate use mechanism allows patients to receive such drugs if no other satisfactory options exist.

But at this point, no one knows how costly the drug might be-or whether it will have unforeseen long-term side effects.

It's too soon to predict what effect endostatin might have on cancer treatment. But the latest gene research has helped us to understand that cancer is not an on-off disease caused by a single cell that goes haywire. It usually manifests as a condition where large numbers of cells become progressively unstable.

It is likely that scientists will discover that endostatin is effective against some tumors at a particular stage in the disease process. As such, the drug could be valuable in treating cancer as a chronic disease, enabling patients to live longer, healthier lives.

"We do not know whether this will be the cure we're all awaiting-or whether that single cure even exists," Klausner says.

Nonetheless, the University of Toronto's Kerbel says, "We may now have a strategy that has a chance of defeating what has always seemed an inevitable and invincible property of malignant tumors."

References

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• Gately S., Twardowski P., Stack M.S., et al. Human aprostate carcinoma cells express enzymatic activity that converts human plasminogen to the angiogenesis inhibitor, angiostatin. Cancer Research 1996; 56:4887-90.
• Gately S., Twardowski P.K., Stack M.S., et al. The mechanism of cancer-mediated conversion of plasminogen to the angiogenesis inhibitor angiostatin. Proc Natl Acad Sci USA 1997; 94: 10868-72.
• Lannutti B.J., Gately St. T., Quevedo M.E., Soff G.A., Paller A.S. Human angiostatin inhibits murine hemangioendothelioma tumor growth in vivo. Cancer Research 1997; 57: 5277-80.
• Nature 390: 404-407. Nov. 1997.