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The Hope & The Hype

14 minute read
Christine Gorman

Unless you have gone through the experience yourself, or watched a loved one’s struggle, you really have no idea just how desperate cancer can make you. You pray, you rage, you bargain with God, but most of all you clutch at any hope, no matter how remote, of a second chance at life.

For a few heady days last week, however, it seemed as if the whole world was a cancer patient and that all humankind had been granted a reprieve. Triggered by a front-page medical news story in the usually reserved New York Times, all anybody was talking about–on the radio, on television, on the Internet, in phone calls to friends and relatives–was the report that a combination of two new drugs could, as the Times put it, “cure cancer in two years.”

In a matter of hours patients had jammed their doctors’ phone lines begging for a chance to test the miracle cancer cure. Investors scrambled to buy a piece of the action, turning the shares of a little company called EntreMed into the most volatile stock on Wall Street. Cancer scientists raced to the phones and fax lines to make sure everyone knew about their research too, generating a new round of headlines and perpetuating the second major medical media frenzy in as many weeks. It was Viagra all over again, without the jokes.

The time certainly seemed ripe for a breakthrough in cancer. Only last month scientists at the National Cancer Institute announced that they were halting a clinical trial of a drug called tamoxifen–and offering it to patients getting the placebo–because it had proved so effective at preventing breast cancer (although it also seemed to increase the risk of uterine cancer). Then preliminary reports indicated that another drug, raloxifene, might prevent breast cancer without triggering new malignancies. Two weeks later came the Times’s report that two new drugs can shrink tumors of every variety without any side effects whatsoever.

It all seemed too good to be true, and of course it was. There are no miracle cancer drugs, at least not yet. At this stage all EntreMed can offer is some very interesting molecules, called angiostatin and endostatin, and the only cancers they have cured so far have been in mice. By the middle of last week, even the most breathless TV talk-show hosts had learned what every scientist already knew: that curing a disease in lab animals is not the same as doing it in humans. “The history of cancer research has been a history of curing cancer in the mouse,” Dr. Richard Klausner, head of the National Cancer Institute, told the Los Angeles Times. “We have cured mice of cancer for decades–and it simply didn’t work in people.”

Even that understates the scientific hurdles that lie ahead. No one knows yet whether angiostatin and endostatin will help people. Even if researchers do figure out how to make the compounds work, pharmaceutical companies estimate it would take as much as $400 million and at least 10 years–not two years–of thorough clinical trials to bring a drug to market.

So what happened last week? On one level this is a case of science journalism gone awry. Although the original story in the New York Times, written by influential science reporter Gina Kolata, was sprinkled with the necessary caveats, it distorted the significance of EntreMed’s research in several important respects, and it exaggerated and romanticized the role of the drugs’ discoverer, Dr. Judah Folkman, a researcher at Children’s Hospital in Boston, in a way that surprised his colleagues and embarrassed Folkman.

But beyond the hype and confusion, something very real is going on. These are exciting times in cancer research, perhaps the most exciting since Richard Nixon declared war on cancer in 1971. Angiogenesis inhibition, the tumor-starving process that Folkman pioneered, is indeed a promising line of research. Dozens of labs are racing to perfect it, some of them doing work that is more advanced than Folkman’s. But it’s not the only field with potential. Just as exciting, say many researchers, is the revolution in cancer treatments made possible by what they’ve learned about how genes and cancer cells work at the molecular level, the fruits of which are already being delivered to human patients (see following story).

How did a story about preliminary data on laboratory animals spiral so completely out of control? The key is Kolata’s piece in the Times and the prominent placement her editors gave it. “Within a year,” she began, “if all goes well, the first cancer patient will be injected with two new drugs that can eradicate any type of cancer, with no obvious side effects and no drug resistance–in mice.” It was a sentence that couldn’t help grabbing readers’ attention–despite those critical two words, “in mice”–and holding it throughout the rest of the story.

Apart from certain omissions, there was nothing factually inaccurate in what Kolata wrote. Folkman, in his statements, went out of his way to downplay his findings. But his carefully cautionary tone was completely overshadowed by the quotes Kolata attributed to a host of other scientists and the adjectives they used to describe Folkman’s work. His results were “remarkable,” “exciting” and “wonderful.” Dr. James Pluda of the National Cancer Institute said he and his colleagues were “electrified” and “almost overwhelmed” by the data.

The quote that nailed the story, however, and put it on the front page, was the one attributed to James Watson, co-discoverer of DNA’s double helix and one of the most famous scientists in the world. “Judah,” he is supposed to have said, “is going to cure cancer in two years.”

That was all the endorsement most journalists needed to hear. The Times wields so much influence as the paper of record–and has a reputation for being so conservative in its news judgment–that few reporters could justify holding their own stories while checking out all the details. And even those who did produce more balanced pieces only seemed to reinforce the impression that something really big had happened. Wire services ticked off the highlights. Television anchors and radio announcers provided the sound bites. And the tabloids dutifully served up the tearful stories of cancer patients desperate to try anything.

Most people thought they were hearing about a new breakthrough. In fact, Folkman’s work on angiostatin and endostatin had been reported months before in scientific journals and just a few weeks ago in Business Week. A November article in Nature briefly boosted EntreMed’s stock 28%, to $15.25 per share. But of course that was nothing compared with last week, when the stock rocketed past $80 before eventually dropping to $33.25 at Friday’s close.

As the week wore on, further complications emerged. In a letter to the Times, Watson denied his remarks. “I sat next to [Kolata] at a meeting at UCLA six weeks ago,” he told TIME. “She never took any notes.” He says he did not tell her that cancer would be cured in two years, although he did communicate his excitement about Folkman’s research.

Kolata stood by her story–as did the Times. “We are entirely comfortable with the coverage and the placement of the article,” says Nancy Nielsen, a spokesperson for the newspaper. As for Watson’s quote: “We don’t wish to get into a quarrel with a respected scientist, but we are confident in the accuracy of our story.”

But things soon got worse for Kolata. On Wednesday the Los Angeles Times suggested that her enthusiasm for Folkman’s work might have been influenced by a potential book deal. She had, in fact, at the urging of her agent John Brockman, dashed off an e-mail message that Brockman told her could, in the hands of the right publisher, be worth a cool $2 million. But after meeting with her editors on Tuesday, Kolata quashed any idea of writing a book. “I did not plan a book,” she says. “I did not write anything that anyone could remotely consider to be a proposal, and any idea was immediately withdrawn.”

Then the New York Post reported that Folkman would share in a $1 million book deal with Random House. Flat wrong, says Random House. It is true that the publisher has tapped science writer Robert Cooke of Newsday to produce a book about Folkman’s life and cancer research and that Folkman has agreed to cooperate with the project. But the scientist won’t get any money from the deal.

What he will get is some hard-won recognition for having single-handedly created the field of angiogenesis. Back in the 1970s, when conventional wisdom among cancer researchers was that most tumors are caused by viruses, Folkman was pursuing his own, very different insight. He noticed that when cancer cells are still tiny–only a millimeter or two across–they don’t need any blood vessels to survive. In order to grow to life-threatening size, however, they need blood. And they get that blood by persuading nearby capillaries to reach out and touch them.

Virtually alone in the scientific community, Folkman decided it would be easier to try to kill a tumor by destroying its blood supply than by attacking it directly. His reasoning was sound. Tumors are made up of rapidly dividing mutant cells that adapt quickly to almost any treatment thrown at them. Blood vessels, by contrast, are made up of normal cells that grow much more slowly and are nowhere near as difficult to outwit. Hoping to starve tumors through their supply line of nutrients, Folkman set out to find a drug that could block the construction of new blood vessels.

At first, he was almost too successful. Everywhere he looked–from cartilage to fungi to the notorious sedative thalidomide–Folkman found one compound after another that exhibited anti-angiogenic properties. But none of them was as effective as he wanted it to be. Then he remembered something that surgeons had often observed: that taking out one big tumor from a patient seems to trigger the growth of lots of smaller ones. Could it be that tumors secrete a substance that inhibits the growth of rival tumors’ blood vessels?

It was such a crazy idea that none of the researchers in Folkman’s lab wanted anything to do with it. Finally one of them, Dr. Michael O’Reilly, agreed to take on the project. Together he and Folkman eventually determined that various segments of a naturally occurring protein called plasminogen seemed to do the trick. They called the collection of molecular fragments angiostatin and found that each version of the compound differed slightly in its ability to stop a tumor from growing.

But no matter what its configuration, angiostatin could not make a mouse tumor disappear. Not, that is, until Folkman and O’Reilly added to the mix a second molecular fragment, which they called endostatin, from yet another naturally occurring protein. Together, the two compounds destroyed a range of tumors in mice. The results were startling enough that they merited testing in people–which is exactly what Pluda, at the National Cancer Institute, intends to do. How fast those studies can begin depends on how much angiostatin and endostatin EntreMed and its business partner, Bristol-Myers Squibb, can produce and whether they can figure out which fragment to focus on first.

At least Folkman doesn’t have to spend all his time nowadays, as he once did, trying to persuade researchers that his approach to cancer treatment has merit. Scientists are currently investigating 300 different substances for their potential to block angiogenesis. Twenty of those compounds have already entered clinical trials in humans. Indeed, researchers suspect that some of the latest cancer treatments, like tamoxifen, may themselves work in part by blocking the growth of newly formed blood vessels.

There are risks involved in messing with the blood vessels. Sometimes angiogenesis is a good thing, especially during pregnancy. One potent anti-angiogenic being studied today is that old scourge thalidomide, which caused so many birth defects in the 1950s by cutting off the blood supply in developing fetuses.

The body also relies on angiogenesis to make new blood vessels during wound healing. That’s a particular concern of people with diabetes, whose cuts and abrasions–particularly in their feet–often take a long time to close, leaving them vulnerable to infection. Fortunately they can use a new prescription cream, the first angiogenesis product to win FDA approval, that stimulates the body’s repair processes and helps those tiny capillaries in their toes and feet to grow.

And although the newest angiogenesis inhibitors have relatively few side effects, at least compared with radiation or chemotherapy, they are not risk free. “Lack of toxicity in animals does not mean there is no toxicity to humans,” says Dr. William Li, medical director of the Boston-based Angiogenesis Foundation, a nonprofit clearinghouse for information on the latest research.

Nor will angiogenesis inhibitors necessarily work equally well against all cancers. The Angiogenesis Foundation has analyzed 29 kinds of solid tumors and discovered that some rely much more heavily on blood-vessel networks than others.

Armed with such knowledge, younger researchers think they can improve on Folkman’s techniques. They prefer a more targeted approach: selectively attacking the various molecules and biochemical signals involved in building a new blood vessel. For instance, researchers at Ixsys, a biotech company in San Diego, have developed an artificial antibody that dissolves the biochemical glue that holds a tumor’s capillaries together. Indeed, one of the patients in their safety study exceeded all expectations when two of the tumors in his abdomen shrank 70%. “I’ve been on the drug now for over a year,” says Barry Riccio, a college professor from Illinois who is suffering from a rare sarcoma. “I have more energy than I did just nine months ago, and I’ve gained back a lot of weight.”

Other researchers are zeroing in on different targets. Some are looking at a specialized growth factor called VEGF (for vascular endothelial growth factor) that so far has been found only in the blood vessels that feed tumors. One synthetic molecule being tested at UCLA prevents VEGF from stimulating new growth by elbowing it aside and taking its place in the cell’s receptors. Safety studies in more than 30 patients have so far not revealed any major side effects, although their tumors’ growth was only slowed, not halted. Dr. Joseph Sparano, at Montefiore Medical Center in New York City, who is pursuing still another approach to anti-angiogenesis, says he doesn’t need to stop tumor growth completely to judge his experiment a success: “If we can make patients with metastatic breast cancer live 20 years and not have symptoms, that may be as good as a cure.”

But it may not be good enough for those millions of cancer patients whose hopes were stirred last week. Hope, for them, is a precious commodity, not something to be rationed or trifled with. Just ask Renee Smith of Dripping Springs, Texas, who three years ago found she has non-Hodgkin’s lymphoma. She has a four-year-old daughter she’d like to see grow up and a husband with whom she’d like to grow old. When friends started calling excitedly last week with news of a possible cure, she resolved to maintain a philosophical calm. “I try to live in the moment because that helps level out the emotional roller coaster,” she says. Still, the moment sometimes escapes her. “I am not perfect,” she says. “I am not the Dalai Lama.” Ironically, it’s patients like Smith, the people most in need of a breakthrough, who were the most vulnerable to last week’s false hopes.

–Reported by William Dowell and Alice Park/New York

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