IMCL, article #2, Chicago Tribune. The biotech race is on:
chicagotribune.com
Driving toward a cure
Chuck Killian travels four hours every day for a test drug that takes a revolutionary approach to attacking cancer
Related links
American Society of Clinical Oncology. (These links will take you out of chicagotribune.com.)
Burnham Institute.
Dana-Farber Cancer Institute: Endostatin clinical trial information.
Genentech, Inc.
M.D. Anderson Cancer Center.
Ribozyme Pharmaceuticals, Inc.
Scripps Research Institute.
Sugen.
UCLA Jonnson Comprehensive Cancer Center.
University of Wisconsin Comprehensive Cancer Center.
Spencer Killian, 8, whispers to her father, Chuck Killian of Mundelein, before he prepares to make his daily drive to the University of Wisconsin Medical Center for endostatin trials. (Tribune photo by Nuccio DiNuzzo)
By John Crewdson
Tribune Staff Writer
February 29, 2000
MADISON, Wis. -- The Grateful Dead blasting from the sound system, Chuck Killian begins the nightly trek home to his family in the Chicago suburb of Mundelein.
As he pilots his black Ford Explorer across five snow-covered counties of Wisconsin and Illinois, Killian, a highly successful 42-year-old insurance executive who still performs with his old college rock band, marvels at what he considers his remarkable good fortune.
"I've always been a lucky guy," he says. "This is like winning the biggest lottery ever."
Chuck Killian has advanced colon cancer, not exactly a stroke of luck. Only a few months ago he was one of thousands of cancer patients around the world vying for entry into three small studies of a widely ballyhooed cancer drug called Endostatin.
Because his symptoms happened to fit the study's profile, Killian is among the nine patients accepted so far by Endostatin researchers at the University of Wisconsin. To receive the daily, hourlong infusions, he cheerfully drives four-plus hours a day, seven days a week.
"I suppose it's a dubious honor," Killian concedes, "because I had to be really sick to get into it. But if this is the cure for cancer, we're right there at ground zero."
Harvard researcher Judah Folkman, in whose laboratory Endostatin was discovered, is credited with having opened a new field of cancer treatment by proving that tumors must create new blood vessels in order to grow.
Dr. Folkman's hypothesis, one of the most exciting in modern medicine, is that cancer can be attacked by choking off its blood supply with molecules like Endostatin, which has strangled tumors in Folkman's mice. Killian is praying it will do the same for the tumors that now reside in his colon, liver and lungs.
Praying along with him are hundreds of thousands of cancer patients who cannot be cured with existing treatments, and whose hopes, like Chuck Killian's, were raised dramatically on a Sunday morning in May of 1998.
That was the day The New York Times quoted James Watson, co-discoverer of the Double Helix, as predicting that Folkman would cure cancer in humans "in two years." Watson later denied making the statement, but the resulting media frenzy conferred extraordinary visibility on a drug that had yet to be tested in a single patient.
No human tumors have vanished since the first Endostatin trial opened in mid-October at the Dana-Farber/Harvard Cancer Center in Boston (the Wisconsin trial began in December). But a number of lower-profile drugs designed to interfere with angiogenesis, as the process of blood vessel formation is known, are farther along the clinical pipeline, and they are already achieving success in a few patients.
A tumor spawns when the genetic machinery inside a cell--a brain cell, a kidney cell, a blood cell, almost any kind of cell--jams, perhaps as a result of years of exposure to cigarette smoke or some other carcinogen. As the renegade cell multiplies, the resulting tumor no longer can draw the oxygen and nutrients it needs from existing blood vessels.
Like a new subdivision laying a water main to the town reservoir, the tumor takes steps to create fresh vessels, hundreds of thousands of capillaries each thinner than a human hair. What Folkman calls the "angiogenic switch" is thrown much sooner than had been imagined, according to a recent report by Duke University's C.Y. Li, who observed angiogenesis taking place through a tiny window implanted in the side of a mouse.
"We see this suddenly, overnight," Li said, "blood vessels forming in the center of a tumor cluster of maybe 300 cells. It's different from what we were expecting."
Cutting the lifeline
Two decades of advances in molecular biology have given scientists the tools to create "smart" drugs that already are showing promise in treating previously intractable cancers. But unlike new drugs that target tumor cells directly, anti-angiogenics are designed to disrupt communications between oxygen-starved tumors and the nearby blood vessels they recruit to lay their lifelines.
The approach taken by Genentech, a San Francisco biotech company, is to intercept and disable a tumor-signaling protein called VEGF before it reaches the blood vessel cells that are its intended target. Genentech won't release its latest results until the American Society of Clinical Oncology meets in New Orleans in May, but researchers working with the company say there have been several complete remissions and a number of partial remissions in patients with the most difficult lung cancer to treat.
Some of Genentech's competitors suggest that striking down VEGF proteins in flight is less efficient than blockading their intended destinations, the docking portals, or receptors, on the surface of blood vessel cells.
"If you're in an auditorium with a thousand people and each of their keys are VEGF, and the locks at the end of the hallways are VEGF receptors, it's a lot less difficult to stick gum in the locks rather than fish out every key from everyone's pocket," says Dr. Samuel Waksal, whose company, ImClone Systems, will soon begin testing a drug, CP1-C11, designed to do just that.
Genentech's San Francisco neighbor Sugen already has such a drug, SU5416. Among patients treated in a small preliminary trial with SU5416 plus chemotherapy, one experienced a complete remission and several had partial remissions.
The VEGF protein is the principal means by which tumors signal their need for blood, but not the only one. As cancers grow and age, many tumors send out more than one kind of signal. Sugen, recently purchased by Pharmacia & Upjohn for $650 million largely on the promise of its anti-cancer research, recently began testing an even newer molecule, SU6668, which blocks blood vessel receptors for VEGF and two other signaling proteins.
SU6668, which is taken by patients in pill form, has occasioned special excitement among researchers because of its spectacular performance in mice, shrinking large tumors to a state Folkman calls "self-sustained dormancy" where they do not grow back.
The only other compound to achieve that result in mice is Endostatin, which must be administered to patients via an intravenous drip.
The SU6668 trials are too new to say whether the drug will help cancer patients as much as it does mice. But Dr. Lee Rosen of UCLA's Jonsson Cancer Center, who is in charge of one such trial, says that the first 16 patients in whom it was tested reported only very mild side effects and that a few advanced tumors appear to have stabilized.
A small Colorado company, Ribozyme Pharmaceuticals, has gone ImClone and Sugen one better, synthesizing a molecule, Angiozyme, that prevents the VEGF receptor from being formed in the first place. In mice, Angiozyme shrinks lung cancer tumors by more than 90 percent. The drug, which showed no toxicity in preliminary trials, is being tested in cancer patients in Cleveland.
One of the few anti-angiogenic drugs not designed on laboratory computers is Oxigene's Combretastatin, derived from the bark of a South African willow tree. Unlike the other drugs, Combretastatin attacks existing blood vessels rather than preventing the formation of new ones. Researchers say initial tests show Combretastatin reduces blood flow to human tumors.
Least promising thus far are drugs aimed at making it impossible for tumor cells and blood vessels to break through the gelatinous material between the body's cells that serves as a natural barrier. In January, British Biotech announced that one such drug, Marimastat, failed to help pancreatic patients live longer than they would have with existing chemotherapy.
The company said it hoped Marimastat would do better in lung cancer patients. But last September, Bayer Corp. announced it was suspending further trials of a similar drug, BAY12-9566, after lung cancer patients receiving the drug relapsed sooner than patients given a placebo.
Hints of effectiveness
Most standard cancer drugs work relatively quickly or not at all.
"In the old system you looked for tumor shrinkage," says Dr. Edward Sausville of the National Cancer Institute, which is financing trials of several of the most promising drugs, including Endostatin. "You cheered when you got it, but you didn't really know why it happened. And no one cared."
Folkman and other angiogenesis researchers point out that because most blood vessel inhibitors only prevent new growth and leave existing vessels intact, tumors may be able to subsist for weeks and months, and even grow a little more, before they begin to shrink.
They worry that the absence of quick, spectacular results in patients will be interpreted as evidence that anti-angiogenics don't work, when it may only be that not enough time has passed to achieve results--or, perhaps, that the results are more subtle than a shrinking tumor.
"It's like turning the sprinkling system off on your front lawn," observes David Cheresh of the Scripps Institute in La Jolla, Calif. "The grass doesn't die right away. You've got to keep that water supply shut off for a fairly long time before you see death in the grass."
Even if anti-angiogenics don't make tumors disappear altogether, in theory many cancer patients should be able to live for years with stable tumors that neither grow nor shrink. The inability to generate new blood vessels would presumably keep tumors from spreading to vital centers like the lungs, liver, brain and bone marrow, the major cause of cancer deaths.
Among the most promising targets for anti-angiogenesis is a class of proteins on the surface of blood vessel cells known as integrins--which, as their name implies, assist in the integration of replicating endothelial cells into new blood vessels.
Cheresh has designed a molecule, Vitaxin, that seeks out and disables a key integrin called alpha-V beta-3, driving the cell down what Cheresh calls a "death pathway" before a new blood vessel can form. "What we've done is simply fooled the system," Cheresh says, "by making the cell think it's stepping out of line by going toward the tumor. Mother Nature will come down with a heavy hand, and that cell is taken out."
Vitaxin has shown what Cheresh calls "significant hints" of effectiveness in cancer patients in small initial trials, and larger trials will begin soon. Within the next few weeks, Kristiina Vouri of La Jolla's Burnham Institute will publish research showing that Endostatin, whose mechanism of action has remained a mystery even to Folkman's laboratory, also acts by binding to alpha-V beta-3 and other integrins.
There is one potentially significant difference that sets Endostatin and its companion molecule, Angiostatin, apart from the other anti-angiogenics: both are naturally occurring proteins produced by the human body for the specific purpose of turning angiogenesis off.
Normal human levels of Endostatin, which is also produced by tumors, aren't high enough in many cases to stifle the new blood vessel growth required to keep primary tumors alive, although Folkman thinks natural Endostatin is responsible for keeping many tumors from spreading throughout the body.
The premise behind the Endostatin trials going on in Wisconsin and Boston and at the M.D. Anderson Cancer Center in Houston is that dosing cancer patients with synthetic Endostatin may raise levels enough to shrink tumors, or at least keep them from growing and spreading.
Trials get under way
Every day around noon, Chuck Killian kisses his wife, Lori, and daughter, Spencer, goodbye and spends the next two hours driving the route he knows well to the University of Wisconsin hospital.
Once on the hospital's clinical research floor, Killian plugs in his laptop and CD player and reclines on a hospital bed while a nurse draws his blood, takes his temperature, checks his pulse, inquires about his disposition and, finally, hooks him up to a machine that takes an hour to infuse about a cup of colorless liquid into his left arm.
Partly because of Endostatin's high profile, Killian and the other patients are among the most closely studied of those in any clinical trial. Their tumors are biopsied regularly, and they are subjected to CT scans, MRIs and X-rays. Their blood is drawn frequently, on some days hourly.
"We're asking a lot of these guys," says Dr. James Thomas, the Madison study's coordinator. "They're really being troupers about this."
Like his counterparts at Dana-Farber and M.D. Anderson, Thomas says it's too early to draw any conclusions about whether Endostatin will work. But the Endostatin researchers agree there's little doubt the drug is safe, at least in the short run.
Before the trial began, researchers worried that if Endostatin turned off angiogenesis in wound-healing as well as in cancer, patients who accidentally cut themselves might bleed to death. That question was resolved when tiny "sham" wounds given to each patient on their upper arms healed normally.
There was also concern that the Endostatin being used in the trial, which is produced in bacterial cultures, might provoke allergic reactions similar to those caused in some people by peanuts and bee stings. It didn't. So far, in fact, none of the Endostatin patients has reported any side effects from the treatment, a remarkable achievement for any potential anti-cancer drug.
The question that matters most, of course, is whether Endostatin is working in people. The answer is it's too early to tell.
So far only 1 of the 9 patients enrolled in the Madison study has been dropped because his tumor grew by more than the 50 percent allowed by the study's guidelines. Thomas says that 8 of 9 patients remaining at this point in a preliminary trial is a higher percentage than usual, but that he doesn't yet know whether it's significant.
It's still early in the Madison trial, which was the last of the three to start. A more interesting story is told in Boston, where 15 patients have now been enrolled in five three-patient "cohorts" a month apart, each group treated with a higher dose than the previous one.
Of the three patients treated with the lowest dose of Endostatin, two dropped out after their tumors grew by more than 50 percent. The third patient, whose tumor had stabilized, could have remained, but left Boston voluntarily to return to his family. Before he departed, X-rays showed evidence of decreased blood flow to his tumor.
One patient in the second cohort also dropped out after her cancer progressed. The two others, however, remain, and in one of them tumors appear to be shrinking after three months of treatment.
Of the third cohort, one patient remains in the study, as do all six patients being treated with the highest doses of endostatin. In retrospect, researchers think the initial doses were set too low, at levels less than half the comparable dose that shrinks tumors in mice. Plans are hastily being made to add a dozen or more new patients to the Boston trial at the top dose.
'. . . dead by Christmas'
Even without any medical evidence, Killian is convinced that Endostatin is responsible for the fact that, since he began daily treatments on Jan. 10, "I feel better physically, intellectually and emotionally than I've felt for a couple years."
The middle finger of Killian's right hand, which had hurt every day since he injured it in a high school football game 26 years ago, stopped aching when the treatments began, and Killian says his blood pressure has dropped 10 points since he entered the study.
Most significant, at least to Killian, is the fact that he no longer is in pain. As recently as Christmas, he says, "I was having pain in my liver daily. The pain in my abdomen was such that I thought I was dying. And that pain has gone away."
Killian, who sometimes wears a T-shirt emblazoned with Judah Folkman's likeness, a gift fashioned by his wife, a former advertising executive, is convinced that fate brought him to Madison.
He had already heard the news about Endostatin by the time doctors at the University of Chicago and Northwestern University told Killian they had nothing to help him. "They said 'Oh, you'll be dead by Christmas,' " recalled Lori Killian. "We said: 'Well, we need to find a different doctor. That's not acceptable.' "
The chemotherapy offered by the Killians' local hospital left Killian "so sick that all I could do was lay on the sofa and moan," he recalls. But it had no effect on his cancer, and by last spring he was out of options.
"I'd been told a couple of different times that I had a year or so to live," Killian says. "It got to the point where Lori and I went out to dinner one night last fall and planned my funeral."
When Killian discovered that his oncologist had trained as a resident in Folkman's laboratory, he decided it was an omen--"that Endostatin is the Holy Grail, that if I could just get into this trial it would save my life."
Killian dialed the 800-number for University of Wisconsin's Endostatin trial, but got a voicemail message.
"So," he says, "I went up there and presented myself and said, 'I will do anything. I am very, very sick with cancer and I am willing to participate in any program you have. And that includes the Endostatin program.' "
Doctors put Killian in another trial while he waited for the Endostatin study to begin. Over the last five weeks the daily round-trips to Madison have put 8,500 miles on his Explorer, but Killian intends to keep making the grueling daily run until the doctors tell him that the Endostatin isn't working or that he is cancer-free.
In the meantime, the respite from the daily pressures of the insurance agency he owns and the added time with his family has given Killian a rare chance, at 42, to reflect on where he has been and where he'd like to go.
"I've had a great life," he says. "I'm not prepared for it to end. But this is very George Bailey-esque. If I recover, I'm going back into mergers and acquisitions in the insurance industry, but I'm going to be nicer about it.
"Now I'm the guy I was before I started to become successful, and that's a good thing. I get a chance to be the guy I dreamed I would grow up to be."
Harvard researcher Judah Folkman is credited with having opened a new field of cancer treatment by proving that tumors must create new blood vessels in order to grow. Folkman's hypothesis is that cancer can be attacked by choking off its blood supply. . |
