Ex-'silver bullet' re-aimed at cancer

Formerly hyped drugs that starve tumors show new promise in use with chemotherapy

By TODD ACKERMAN, May 16, 2005
Copyright 2005 Houston Chronicle

ORLANDO, Fla. - It was hailed as cancer's potential silver bullet in the late 1990s, only to become the latest failed hope at the start of the 21st century.

But anti-angiogenesis therapy based on starving tumors to death by choking off their blood supply has reappeared on the cancer-care landscape, and this time more realistic expectations figure to keep it around.

No longer a "cure," its new uses against cancer have given it some buzz at the annual meeting here of the American Society of Clinical Oncology.

"It's here to stay," Dr. Roy Herbst, a University of Texas M.D. Anderson Cancer Center thoracic oncologist and one of the field's leaders, told meeting participants during the weekend. "It's not just the future. It's now."

Now used in combination with chemotherapy, the new treatment is making inroads against some of the deadliest cancers. Researchers reported impressive results from Avastin, the field's star drug, for mesothelioma, lung, breast and ovarian cancer. The FDA approved Avastin for the treatment of colon cancer in 2004.

So complementary is Avastin with chemotherapy that in time, Herbst thinks, it will become the most-used cancer drug in the world. Just at M.D. Anderson right now, about 25 doctors are studying to see if Avastin will help in six other cancers.

Even more are studying other anti-angiogenesis agents. All told, roughly 1,000 laboratories around the world today are studying anti-angiogenesis, and more than 300 biopharmaceutical companies have drugs in development.

Those weren't the expectations a few years ago, after the therapy failed in trials. Suddenly, a different kind of targeted drugs were all the rage, drugs with names like Gleevec and Herceptin, drugs that attack tumors at the molecular level.

Anti-angiogenesis works at the molecular level, too, but it targets a tumor's food supply instead of the tumor itself, interfering with the process by which a tumor "signals" already existing blood vessels to sprout new branches to feed it, an otherwise effortless process given the amount of blood flow already in place in the human body. Without that connection, tumors grow to a mere 1,000 cells and stop.

"It's like if you have 10 houses in a block and you decide to build 50 more, they can't exist on the same water supply — they need more pipes," said Dr. Judah Folkman, a researcher at Children's Hospital in Boston and the man most responsible for the field. "The beauty of stopping that process is that it makes it possible to treat the disease without ever even seeing the tumor."

Early expectations

It was Folkman's quixotic dream, dating to the 1970s, that led to anti-angiogenesis. Virtually alone in the scientific community, he pursued the idea and finally in one experiment, two of his drugs eradicated cancer in all 10 mice in which they were injected. In 1998, the New York Times ran a front-page story on the experiment and quoted Nobel laureate in medicine James Watson saying Folkman would "cure cancer in two years."

But the drugs failed in human trials, proving scientific adages about the difference between curing cancer in mice and people. Drug company stocks, which had soared after the Times' story, plummeted.

In retrospect, say specialists in the field, it shouldn't have come as a great surprise. The expectations were too high, the trials involved people whose cancers had already formed elaborate blood vessel networks and more work was needed to determine the best doses and targets and in what combinations with other medicines the drugs worked best.

Nature of treatment

It also had something to do with the nature of the treatment. Most traditional cancer treatments, such as chemotherapy, deliver a toxic punch on cancer cells that makes their effect readily measurable.

But anti-angiogenesis agents are designed to quietly interrupt a molecular process that leads to cancer development or growth. It's not always easy to know if they're working — they may not shrink a tumor immediately but instead slow its growth or stop it from spreading.

That's what Avastin has done for Ciro Treviño, a 51-year-old Edinburg school administrator with stage 4 colon cancer. M.D. Anderson put him on Avastin and chemotherapy in August and the disease has stabilized.

"I'm very happy with it," said Treviño, whose wife's research on the Internet alerted him to anti-angiogenesis when he first received a cancer diagnosis in 2003. "I've had very few side effects and I've been able to maintain a high quality of life."

'Living proof'

Another M.D. Anderson patient, John Brooks, flew from his home in Arizona to the Orlando ASCO conference Sunday to meet with Herbst, Folkman and other doctors about his next line of treatment.

Diagnosed with sarcoma in 1988, he calls himself "living proof that anti-angiogenesis isn't a failed experiment." He is the only surviving patient from one of Folkman's original drug trials.

Although M.D. Anderson was involved in only one of the Avastin studies presented at ASCO, it probably conducts more anti-angiogenesis research than any other institution, including lab work or trials on an alphabet soup of experimental agents such as BAY 43-9006, AGO 13736 and AZD 2171. In one year alone, 2002, the National Cancer Institute awarded it more than $9 million for anti-angiogenic research.

Among the drugs being tested by M.D Anderson is thalidomide, the morning-sickness reliever that caused birth defects in the 1950s.

Only in the mid-1990s did researchers wonder if the very quality that damaged the growth of limbs in developing babies might be helpful in preventing tumors from promoting blood vessel formation. It's being tested for prostate cancer, multiple myeloma, brain and ovarian cancer.

Shark cartilage

Another involves shark cartilage, one of the most-hyped natural products of the 1990s. Shark cartilage belongs to a class of anti-angiogenesis drugs that are designed to directly "kill" the blood vessels that feed tumors, unlike Avastin and most under testing that block the signals cancer cells send to lure blood vessels.

M.D. Anderson is leading a nationwide Phase III lung cancer trial of a product extracted from shark cartilage.

Still, anti-angiogenesis has a long way to go. Researchers only recently recognized that blood vessels are not uniform and generic, like plumbing in a house, but strikingly different and particularly unusual in tumors. That may explain why even Avastin only benefits some patients.

Though it doesn't have the debilitating side effects that characterize chemotherapy, anti-angiogenesis drugs can have serious drawbacks.

Avastin, for instance, can cause blood clots that lead to strokes or fatal bleeding in the lungs.

The lung cancer study presented at ASCO included eight deaths from such bleeding, even though a third of people with the type of lung cancer targeted were eliminated because they were considered at-risk.

Confident of progress

But Herbst, noting how new anti-angiogenesis agents are better than the original ones, is confident the drugs will be perfected as research progresses.

He foresees them being used in conjunction with not just chemotherapy, but other smart drugs, as well as surgery and radiation, until perhaps one day anti-angiogenesis drug "cocktails" are all that's needed.

"Thanks to the recent successes, I think there's great excitement now about anti-angiogenesis,"said Dr. Lee Ellis, an M.D. Anderson professor in the departments of surgical oncology and cancer biology. "The mood change has been huge."