Cancer Breakthrough

The grandfatherly American with thinning hair who addressed cancer scientists in a Montreal hotel earlier this month did not look like someone about to set off an international media frenzy. Dr.

Cancer Breakthrough

The grandfatherly American with thinning hair who addressed cancer scientists in a Montreal hotel earlier this month did not look like someone about to set off an international media frenzy. Dr. Judah Folkman talked about his work in a fast-developing field that seeks to defeat cancer not by destroying the tumors themselves but by attacking the blood vessels which nourish them. With wry humor, Folkman talked about the difficulty he had a few years back persuading someone in his Boston laboratory to take on an assignment that could easily have ended in failure - everybody on his team was just too busy. In the end, the study was done, paving the way for prototype drugs that can virtually obliterate tumors in mice with negligible side-effects, and without encountering the defences that fast-mutating cancer cells often throw up. "Most of us already knew about Judah's work," said Dr. Lorne Brandes, a Winnipeg cancer researcher who heard Folkman in Montreal. "So none of this was earth-shaking news. It looked impressive - but so far the results are only in mice."

Beyond the confines of the cancer-research community, however, it was a sensation. After a May 3 article in The New York Times described the new drugs - angiostatin and endostatin - a media earthquake rocked Folkman and his laboratory at Boston Children's Hospital. The massive coverage, in turn, prompted telephone calls from cancer patients to physicians and institutions pleading for access to the drugs. At the U.S. National Cancer Institute in Bethesda, Md., director Dr. Richard Klausner called Folkman's findings "the single most exciting thing on the horizon" for treating cancer.

He promised fast-track handling for human trials of the drugs - although officials of Rockville, Md.-based EntreMed Inc., which will manufacture them, said it could be up to 18 months before enough is available to begin wide-scale human testing.

Even if trials show the drugs to be safe and effective in humans, several years could pass before they win regulatory approval and begin reaching patients. But the uncertainties and the time frame were no deterrent to investors who saw a wonder drug in the making. EntreMed shares trading on the Nasdaq network soared to around $115 from $17.25, before settling back to $47.88 by week's end.

Amid the euphoria, cancer experts - including a Canadian physician who played a role in Folkman's work - were virtually unanimous in stressing that the new drugs might not work as well in humans as in mice. "These findings have to be treated with extreme caution," said Dr. Robert Kerbel, a researcher at Toronto's Sunnybrook Health Science Centre whose earlier suggestion of a strategy for defeating drug resistance in cancer was vindicated by Folkman's work. "We have a long history of drugs that can do a great job of attacking cancer in rodents - but don't work as well in humans."

Apparently dismayed by the frenzy of media attention, Folkman himself cancelled a speaking engagement in Boston and issued a caution of his own. "We know the proteins work on mice," he said. "But the important thing is determining whether they will work on people."

Among cancer sufferers, including those in Canada, where an estimated 62,700 people will die of the disease this year, reports of the drugs' remarkable success in laboratory tests stirred hope. Too much hope, for some specialists' liking. Dr. Anthony Tolcher, a medical oncologist at the British Columbia Cancer Agency in Vancouver, said a prostate cancer patient wanted to know whether his treatment could be suspended until the new drugs were available. "I told him to forget he'd heard of these drugs," said Tolcher. "Even if they work in humans, it will be years before they're available."

A veteran cancer researcher, Folkman first proposed in 1970 that cancer might be beaten by blocking angiogenesis - the process that enables tumors to grow the blood vessels they need to supply them with oxygen and other nutrients. Greeted initially with skepticism, the idea has gradually won wide support. In fact, drug companies are testing scores of potential anti-angiogenesis drugs - including one called SU5416 that researchers at the University of California at Los Angeles say has shown promising results in trials involving about 30 people.

Folkman, meanwhile, has pursued a particular approach to thwarting angiogenesis. It is based on the notion that tumors not only promote the growth of new blood vessels but - for reasons that are not clearly understood - simultaneously block their formation in other potential tumors when cancer cells have spread elsewhere in the victim's body. Folkman persuaded a researcher, Dr. Michael O'Reilly, to search for the proteins that inhibit blood vessel growth, and O'Reilly identified one of them - angiostatin - in 1994. Later, Folkman's team isolated a second inhibitor, endostatin.

The discoveries made it possible to attack tumor growth - and to test a hypothesis put forward in 1991 by Kerbel suggesting that, while eradicating tumors, agents like Folkman's might have the added bonus of not being susceptible to drug resistance. In an article published in the British journal BioEssays in January, 1991, Kerbel speculated that a drug that did not attack the tumor cells but instead zeroed in on the cells lining blood vessels - as angiostatin and endostatin do - might avoid being rendered ineffective by rapid mutation of the target cells. The idea popped into Kerbel's mind during a conversation with a graduate student who found it frustrating that many promising cancer drugs were ultimately defeated by drug resistance. "A light went on in my head," recalls Kerbel. "Because cancer cells divide rapidly, they can develop drug-resistant mutations. But if you were targeting normal cells, like the cells lining blood vessels, they should be less likely to become resistant."

Kerbel discussed the idea with Folkman, who said he had not thought of it. Now, Folkman's work has shown that Kerbel was right - and demonstrated as well that, in mice, the new drugs can make tumors dwindle to the point of near-invisibility. In an article last November in the British journal Nature that was little noticed outside scientific circles, members of Folkman's team described how tumors in mice shrivelled and became dormant after repeated injections with endostatin.

If the new anti-angiogenesis drugs work in humans, they could prove to be a turning point in the war on cancer. Even though cancer rates are rising, patients are surviving longer, thanks to earlier detection and better treatment. Doctors cite the development of equipment capable of delivering higher doses of cancer-killing radiation more accurately, as well as improved surgical techniques that can help save victims of breast, cervical, lymphatic, prostate and other forms of cancer. Drugs also play a prominent role in combating cancer - among them, six-year-old taxol used to treat ovarian cancer following surgery and cisplatin, first marketed during the late 1970s, which can help to beat some cases of testicular cancer in men.

But experts point out that, over the years, a succession of substances touted as potential miracle cures - interferon and interleukin-2 during the 1970s and 1980s and, more recently, synthetic monoclonal antibodies designed to mobilize the human immune system - have fallen far short of expectations. In the war on cancer, says Dr. Don Cowan, a vice-president of the provincial agency Cancer Care Ontario, "explosive breakthroughs are rare - it's mostly a matter of steady, step-by-step improvement."

The ultimate importance of the substances discovered in Folkman's lab can only be determined by the clinical trials that lie ahead. But will they deliver more than the many hoped-for "silver bullets" of the past? "What I suspect," says Kerbel, "is that the results in humans may be good - but not nearly as dramatic as in mice." And Folkman himself says he foresees angiostatin and endostatin being used in conjunction with existing treatments, including surgery and radiation. It is a worthy role, but one that falls far short of the panacea dreamed of by cancer sufferers everywhere.

Maclean's May 18, 1998