Here's the US News & World Reports story:
Cover Story 5/18/98
Killing Cancer
New drugs can cure mice, thanks to advances in understanding the disease's basic biology. But cures for people are still years away
BY SHANNON BROWNLEE AND NANCY SHUTE
Like any scientist whose work has been mired in controversy, Judah Folkman dreamed of proving his critics wrong. But he didn't plan on success unfolding quite this way. For two decades, he'd endured the ridicule of colleagues, who called him a clown and said his theory of cancer--that malignant tumors needed a blood supply in order to grow--was "dirt." The surgeon and cell biologist at Children's Hospital in Boston persevered nonetheless, spending mornings in surgery and afternoons hunched over a laboratory bench. Finally, after years of laborious and often frustrating research, Folkman, 65, had in hand two compounds that could wipe out large tumors in mice by cutting off their blood supply, proving his theory and opening the possibility of a revolutionary new way of treating cancer.
But when the New York Times featured his work on the front page last week, Folkman suddenly got far more attention than he'd ever bargained for--or wanted. In the next days, headlines across the country blared, "Cancer Cure." Share prices soared on the stocks of a dozen biotechnology companies hoping to bring Folkman's drugs and similar compounds to market (box, Page 64). Interview requests poured in to Children's Hospital from media outlets around the world. And phones and fax machines in Folkman's office were jammed by up to 1,000 calls a day, many of them urgent pleas from desperate cancer patients and their relatives, hoping for a chance to try the new drugs.
There was only one problem: Folkman's drugs, called angiostatin and endostatin, are not the "cure" for cancer--at least not yet. The drugs work spectacularly well in mice, shrinking cancers that would be the equivalent of a 1-pound tumor in a human being. But, as one doctor said, if curing mice were all that was needed, the war on cancer would have been won long ago. Folkman's drugs are the most potent among a throng of similar compounds discovered in the last decade, all aimed at choking off the growth of blood vessels around a tumor, causing it to shrink. But the new drugs have many hurdles to clear before they can begin helping patients--not the least of which is to be produced in quantities large enough to be tested in people. There is no guarantee they will work in human beings, or work as well as they do in mice. The road to eliminating cancer is littered with failed drugs that once were hailed as cures. And even if the drugs are found to be effective, it will be several years before doctors can prescribe them for their patients. As Folkman himself wearily repeated over and over again last week, the only sure bet is: "If you are a mouse with cancer, we can take good care of you."
"Terrifically exciting." That said, most cancer researchers believe Folkman's discoveries truly are revolutionary and that they do in fact offer a novel strategy for curing cancer--though the "cure" may not come as quickly as the public would like. "This is terrifically exciting," says Helene Sage, a cell molecular biologist at the University of Washington. At a meeting in Bethesda, Md., late last year, Folkman presented data that prompted Richard Klausner, director of the National Cancer Institute, to give the drugs the highest priority for clinical testing. Even Folkman himself says, "I've been waiting for results like these my whole life."
Some of the enthusiasm among scientists stems from the fact that Folkman's drugs are helping to validate scientists' efforts over the last 30 years to understand cancer's basic biology. When Richard Nixon declared war on the illness in 1971, biologists knew precious little about how cancer worked on a cellular level, and oncologists had only the blunt tools of radiation, surgery, and chemotherapy to work with. Oncologists still don't have a lot of weapons at their disposal, but new understanding has spawned promising treatments, including gene therapy and monoclonal antibodies, the first of which went on the market late last year.
The insight that inspired Folkman to begin his search came long before biologists began to peer into the interior of a tumor cell. Clinicians knew that once a tumor grows beyond a few hundred thousand cells--no bigger than a BB--the cells at the center of the mass start to die. Folkman surmised that to grow, tumors need blood and send out an unknown substance that coaxes nearby blood vessels into sprouting new capillaries--a process known as angiogenesis, from the Greek angos, for vessel. But other clinicians, still wedded to the notion that the infiltration of a tumor by blood vessels was merely an unimportant side effect, scoffed at the idea.
Folkman proved the skeptics wrong in 1983, when two postdoctoral fellows in his lab purified a protein from a rat tumor that did precisely what he'd predicted, stimulating the growth of capillaries. There are now at least 14 known angiogenic factors. They cause blood vessels to sprout new branches and give tumors the double benefit of a rich supply of blood and proteins, produced by blood vessel cells, that also help cancer cells grow.
Folkman reasoned that if he could somehow block the tumor's blood supply, the cancer could be stopped. Soon after, he quit performing surgery and focused his attention full time on searching for a protein to do just that by inhibiting the growth of capillaries.
Serendipity. In 1985, he got a lucky break, when blood vessel cells being cultured in the lab were accidentally contaminated by a yeast that stopped the cells from growing but didn't kill them. Folkman's team isolated from the yeast a naturally occurring substance called fumigillin, which could slow down tumor growth when injected into mice, and which simultaneously proved Folkman's principle and transformed his critics into competitors. Synthetic versions of fumigillin have been shown safe in people and have a weak ability to slow tumors.
Since then, Folkman's lab and others have found dozens of antiangiogenic factors, some of which are already being tested in people, including thalidomide, banned in the 1960s after causing devastating birth defects, and alpha interferon, touted as a cancer cure in the late 1970s. Both these drugs, it turns out, have antiangiogenic properties and can inhibit blood vessel growth. Alpha interferon is now showing limited success battling slow-growing tumors of the bone and life-threatening hemangiomas, a childhood cancer. But the drug can't knock out tumors that are more malignant, says Folkman. "Breast cancer would laugh at interferon."
The scientist's new drugs, by comparison, are prizefighters. Their success rests upon a clinical observation that has baffled doctors for years: In some patients, the largest tumor in the body seems to stunt the growth of metastatic tumors, the tiny progeny of the original tumor that take up residence in far-flung sites in the body. Removing the largest tumor surgically in very rare cases allows the little tumors to spring to life, growing so rapidly they can kill the patient before doctors can suppress them. Folkman and his team realized that perhaps the main tumor was itself sending out antiangiogenic factors. These substances then traveled outward, blocking the blood supply to the little tumors and inhibiting their growth.
In the next years, this inspiration was fleshed out by the meticulous drudgery that makes up most of scientific research. A young doctor named Michael O'Reilly teamed up with the University of Washington's Sage and Yuen Shing, a protein chemist in Folkman's lab, and together they poured milliliter after milliliter of mouse blood through glass tubing, searching for a protein that might be a long-distance blocker of blood vessels. Eventually, they found two. O'Reilly then had the task of extracting from mouse urine, where the proteins are plentiful, a sufficient amount of them to treat a few mice. "He smelled so bad that his wife made him take his clothes off before he came in the door after work," Folkman recalls.
O'Reilly's efforts paid off. The proteins, angiostatin and endostatin, could shrink a mouse tumor the size of an almond--much too big to be killed by chemotherapy--to almost nothing in a few days. Working in tandem, the drugs brought about a cure. Best of all, angiostatin and endostatin seem to home in on capillaries near cancer cells, leaving blood vessels in the rest of the body alone, and causing the mice no apparent side effects. Unlike traditional chemotherapy, which can make mice as well as human patients quite ill, endostatin, angiostatin, and vasculostatin, Folkman's newest find, appear benign. They are also, in contrast to standard chemotherapy, likely to keep on working even if they are given to patients for many years. Cancer cells mutate at a furious rate, and they can evolve the means to resist most chemotherapy drugs, requiring higher and more toxic doses to achieve an effect. Antiangiogenic factors do not seem to induce resistance in slower-growing blood vessel cells, but Folkman admits that no one knows precisely how they will work in humans.
Frantic calls. Last week's New York Times article is still reverberating in doctors' offices, where phones and faxes have been ringing with calls from patients begging for the new drugs. "These new drugs are all our patients want to talk about," says David Van Echo, an oncologist who heads drug development at the University of Maryland--Baltimore. "They are saying they want to get the new drugs and they don't want the treatment they're taking."
It is not a wish that will be granted anytime soon. For one thing, there is hardly enough angiostatin and endostatin in the world to treat a few mice, let alone millions of human patients suffering from cancer. And even if there were, the drugs must first run the gantlet of clinical trials--the careful, government-mandated tests that are the only way to determine if new medicines are safe and effective in people. At least 25 companies are racing to bring versions of antiangiogenic compounds to market, including pharmaceutical giants SmithKline Beecham, Merck, and Novartis, as well as biotech start-ups like Boston Life Sciences and EntreMed, the firm that was founded in order to commercialize angiostatin and endostatin. Some of the new drugs have already entered the early phases of clinical trials, which can take from five to seven years to complete. Endostatin and angiostatin are at least 1« years away from human tests, says an EntreMed spokeswoman, because the company has yet to work out the kinks to produce large amounts.
Many other obstacles lie between curing cancer in mice and battling tumors in human beings. Mouse tumors, says Martin Brown, a professor of radiation oncology at Stanford University Medical Center, grow extremely rapidly, and they are totally dependent on new capillaries. "I don't want to minimize Judah Folkman's work," he says. "There's a good chance these drugs will be active against human tumors. But it will not be as dramatic in humans as in mice, and human tumors will shrink more slowly." Other researchers warn that the drugs may cause side effects in people, like muscle inflammation. And antiangiogenics might cause birth defects if a woman takes them while she is pregnant, as other anticancer agents do.
If they finally come to market, the new drugs will join a variety of other new cancer treatments, many of which are already being tested in humans. In killing cancer, the key problem remains that standard cancer treatments such as radiation and chemotherapy damage many cells in the body, not just the cancerous ones. More recent experimental therapies tightly target newly identified molecular and genetic pathways within cancerous cells, rather than using the broad-spectrum attack of older therapies. Later this month, biotech giant Genentech will unveil the first evidence that a genetically engineered monoclonal antibody, to be marketed as Herceptin, mimics key components of the body's immune system and shrinks breast cancer tumors in women. Herceptin attacks the HER-2 gene, which generates a protein that boosts cancer growth in about 30 percent of patients.
Since the 1940s, researchers also have been trying with little success to stimulate the body's immune system to fight cancer by administering vaccines made of malignant cells. But in the past decade, researchers have devised vaccines, cobbled together from either whole cancer cells or pieces of cells, which boost an immune response against the tumor. In human trials at Jefferson Medical College in Philadelphia and elsewhere, the vaccines have proven as successful as aggressive chemotherapy against melanoma, but without the debilitating side effects. Dozens of similar vaccines are in the works targeting other cancers.
One of the most promising new cancer treatments is gene therapy. In the 1970s, scientists began to figure out that mutated genes are the triggers that turn normal cells into cancer cells, growing out of control. If the damage could be fixed, or the bad genes could be replaced with good copies, they reasoned, the cell proliferation could be stalled. Current gene therapy efforts are aimed at the three classes of genes that go bad in cancer: oncogenes, which stimulate cell growth and division; tumor suppressor genes, which restrict cell growth; and another type of gene that controls DNA replication and repair. Gene therapy has generated huge interest and millions of dollars of funding, but until recently has been criticized as overhyped, because no one could find a method for delivering enough genes into cancer cells without producing toxic side effects.
Catch the bus. Later this month, however, researchers from the University of Texas M. D. Anderson Cancer Center in Houston will present results showing for the first time that gene therapy can in fact repair damaged genes and suppress tumors. The researchers drafted the adenovirus that causes the common cold into service as a bus, carrying the p53 gene into cancer cells. The p53 gene puts the brakes on cell growth and forces cells to commit suicide if their DNA is damaged, for instance by sun exposure or smoking. Last year, the adenovirus-p53 combo was tested in almost 100 patients with head and neck cancer, and tumors shrank in almost 50 percent of patients. "There was very little toxicity, even with monthly injections," says Jack Roth, the thoracic surgeon who led the study. "It was a little surprising." P53 gene therapy is also being tested on lung and prostate cancers, and is expected to go into clinical trials by the year 2000.
Another experimental treatment, anti-sense therapy, may not drive tumor cells to commit suicide, but it seems to slow them down. Anti-sense molecules are threads of nonsense DNA that derail oncogenes by jamming their message and canceling the order for growth-promoting proteins. Anti-sense drugs are in clinical trials in ovarian cancer and others. Research on still another substance, an enzyme called telomerase, isn't nearly as far along, but researchers are excited about its role in controlling the life and death cycle of all cells, including cancer cells. All DNA strands are capped by telomeres, extra bits of DNA that snap off piece by piece every time a cell divides. Once the telomeres are gone, the cell stops dividing and grows old. In January, researchers at Geron Corp. in Menlo Park, Calif., proved that the enzyme telomerase lengthens telomeres, enabling the cell to keep dividing. Cancer cells draft telomerase to keep themselves going. Geron and other firms are working on ways to block telomerase in cancer cells to force them to age and die like normal cells.
Old and new. At least a few of these new therapies are likely to make it to the market long before Folkman's antiangiogenic drugs become available. But none of the new treatments, including Folkman's, will put an immediate end to chemotherapy and radiation. Instead, old and new will be used side by side, delivering a one-two punch to tumors. "I'd love to put radiation and chemotherapy out of business, but it's not happening anytime soon," says John Mendelsohn, an oncologist and president of the M. D. Anderson Cancer Center. "We're still going to need all the help we can get, at least over the next five to 10 years."
Folkman, for his part, envisions a time when doctors will hit tumors with an antiangiogenic drug to knock them down in size, surgically remove the tumors, then deliver more antiangiogenics along with chemotherapy or gene therapy to wipe out metastatic tumors. Long-term use of antiangiogenic drugs might be able to keep some tumors dormant so they never pose a threat. But that's all in the future. For now, the scientist just wants to get back to the lab and resume his search for even more powerful cancer killers.
With Laura Tangley |
