Starving Tumors To Death

A new approach cuts off cancer's blood supply

Medical researchers searching for a "magic bullet" that could treat cancer without poisoning the patient may be on to something. Instead of using chemotherapy or radiation to attack the tumor, they're trying to starve it to death. More than a dozen drugs currently under development have shown remarkable success in treating breast, brain, and lung cancers in mice by blocking blood vessel growth to tumors--essentially cutting off their life-support system. Even more exciting, some of these compounds have eradicated cancer in mice altogether.

This elegantly simple approach is one of the hottest areas in cancer research, with some 25 pharmaceutical and biotechnology companies around the world working on it. Outfits ranging from drug giants such as SmithKline Beecham, Merck, and Novartis to startups EntreMed, SUGEN, and British Biotech are all testing compounds that block a process called angiogenesis, the growth of new blood vessels. These drugs could address a much broader range of cancers than most existing drugs, which are usually highly toxic and work only against one or two types of cancer. The new drugs--called angiogenesis inhibitors--block the chemical signals that tumors send out to attract new blood vessels. Because the signals are the same across a broad range of cancers, the drugs should stop almost any kind of cancer.

MEGAMARKET. With more than 1 million new cancer cases diagnosed each year in the U.S., the market for angiogenesis inhibitors could be enormous. The compounds are also being tested against macular degeneration, a common cause of blindness in the aged that occurs when blood vessels grow over the cornea, and which afflicts an estimated 13 million Americans. Wall Street analysts predict that an angiogenesis inhibitor could be the first cancer drug to reach blockbuster status, with annual sales exceeding $1 billion.

At least 9 of the 12 or so compounds found to inhibit the growth of new blood vessels to cancer tumors are already in clinical trials. They include the controversial drug thalidomide, marketed as a sedative in the 1960s before it was found to cause horrific birth defects when taken by pregnant women. Researchers discovered in 1992 that thalidomide blocks blood vessel formation, which is why it caused birth defects in the first place--it cut off blood vessel formation in the fetus. Now, in clinical trials being conducted by the National Cancer Institute, the drug is showing promise against the toughest tumors.

To avoid the problems of thalidomide and other first-generation compounds, the new group of angiogenesis inhibitors targets blood vessel growth more specifically, offering the promise of powerful cancer drugs virtually free of toxic side effects. A recent Lehman Brothers Inc. study that examined a variety of new cancer treatments concluded that angiogenesis inhibitors are the ones likely to "provide the foundation for cancer therapy in the future."

The explosion of interest in these drugs was evident at a meeting of the American Association for Cancer Research in New Orleans in March, where researchers presented some 50 papers on the subject, up from a handful a year earlier. Among the most startling was a report by Dr. Erkki Ruoslahti, president of the Burnham Institute, a nonprofit research center in La Jolla, Calif. He described a "one-two punch" that knocked out cancer in mice permanently. Ruoslahti's team combined doxorubicin, a widely used chemotherapy drug, with an angiogenesis inhibitor called tumor homing peptide (THP).

The mice implanted with human breast cancer cells that received Ruoslahti's compound, called THP-dox, showed no recurrence of cancer during their lifetimes, while the mice receiving only doxorubicin died either of drug poisoning or tumors that developed drug resistance. "This is one of the most exciting pieces of work I've seen recently," says Donald S. Coffey, professor of oncology research at Johns Hopkins University School of Medicine. "He really seems to have finally beaten the resistance mechanism." THP-dox has been licensed to ILEX Oncology Inc., which is aiming for clinical trials in two years.

Despite these early successes, researchers have a long way to go from mouse to human, cautions Dr. James M. Pluda, senior clinical investigator of the National Cancer Institute's investigational drug branch. "The field of oncology is littered with the bodies of agents that were the next magic bullet," he says. But, he adds, "I think this form of therapy may be an important weapon in our arsenal against cancer."

Dr. Judah Folkman of Children's Hospital, Boston, first theorized that cancer tumors depend on angiogenesis 30 years ago. But it is only in the last five years that molecular biologists have been able to isolate the cell mechanisms that trigger the process.

Blood vessels normally have only one big growth spurt, in the fetus. After birth, there are three instances in a healthy person when new capillaries sprout--menstruation, pregnancy, and wound healing. The big exception is cancer. When rogue cancer cells first emerge in the body, they rapidly divide and form a tumor about the size of a pea--too far away from the surface of any existing capillary to receive nourishment. This tumor can remain dormant for several years. But at some point it starts sending chemical signals to the endothelial cells that make up blood vessels. In response, new capillaries are formed that reach out to the tumor, carrying nutrients and oxygen. The tumor starts expanding, sending cancer cells along the capillaries until they spread throughout the body.

OFF SWITCH. Sometimes, however, that first tumor also sends out signals that suppress the formation of secondary tumors elsewhere in the body. In that case, the tumor applies chemical "brakes" that put a stop to capillary growth. Folkman and colleague Michael O'Reilly have isolated two of these primary tumor brakes, proteins called angiostatin and endostatin, and cancer experts say they may be the most powerful angiogenesis inhibitors yet.

Last November, O'Reilly reported that he could eliminate some tumors altogether in mice by using endostatin and angiostatin in combination. But he had only minute amounts of the two proteins, which he had painstakingly isolated from mouse urine. Rockville (Md.)-based EntreMed Inc., which underwrites Folkman's research, has taken a big step toward commercialization, however. The company announced at the recent cancer research meeting that it had successfully produced a bioengineered version of angiostatin, licensed to Bristol-Myers Squibb Co., that will be available in much larger quantities. Kim Lee Sim, senior director of molecular biology at EntreMed, says the recombinant version of angiostatin reduced the number of melanoma tumors in mice by 60% to 80% after 11 days of treatment, and those that remained were tiny. "We've effectively turned off a switch that the body turned on," says EntreMed Chairman John W. Holaday.

To keep that switch off permanently, scientists from Genetix Pharmaceuticals Inc. in Cambridge, Mass., introduced the genes for endostatin and angiostatin into the bone marrow of tumor-infected mice. After 12 weeks, they reported that the mice still carried the proteins and their tumors were reduced dramatically. The gene therapy approach, says Genetix scientist Dr. Robert Pawliuk, empowers the body to make its own cancer-fighting proteins, eliminating the need for daily injections.

There are other angiogenesis inhibitors under development and a steady stream of promising new studies. At the New Orleans meeting, researchers from TAP Pharmaceuticals of Japan reported that their TNP-470 compound prevented the spread of lung and skin cancers in mice during 20 days of treatment. Japanese researchers demonstrated that another inhibitor showed high potency against human stomach tumors that had been implanted in mice. And a team from Monsanto Co. reported on yet another compound as safe and effective against solid tumors in mice.

There were also reports on compounds derived from shark cartilage, a cancer folk remedy long dismissed as ineffective by medical experts. But researchers have found some proteins in shark cartilage that do block blood vessel formation. Bioengineered versions include Neovastat, made by Aeterna Laboratories of Canada; squalamine from Magainin Pharmaceuticals in Plymouth Meeting, Pa.; and Troponin I, from Boston Life Sciences in Boston. All have dramatically reduced the size of tumors in mice without toxic side effects.


A lot of work still needs to be done before the newest angiogenesis inhibitors are proven in humans. Most of them are expected to enter clinical trials later this year, and it will be four or five more years before they could win approval--if the trials are successful. But researchers say the angiogenesis inhibitors have already had a tremendous impact on the way laboratories are thinking about cancer. "There are two ways to make an organism extinct. Knock each one out individually or knock out its habitat," says Coffey. "The second way is a lot more effective." Someday, researchers hope, that change in thinking will lead to a dramatic change in treatment.

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