Pressing ahead to battle tumors

It was a brand-new approach to fighting cancer: Instead of attacking tumors directly, clinicians would starve them to death by cutting off their blood supply.

Then came the first, early human trials, and the results were lackluster. Had the hope for this approach -- known as anti-angiogenesis -- evaporated before the ink had even dried on the celebratory reports?

Scientists say that isn’t the case. Anti-angiogenesis remains a leading, novel way to fight cancer and is being pursued by researchers and drug companies. They caution, however, that nobody should expect any miraculous, blanket cures from such drugs (or any other drug, for that matter).

“I think this is typical of any field in oncology: You make some preliminary observation and exciting laboratory discoveries, and there is probably this excessive hype generated,” said Dr. Przemyslaw Twardowski, staff physician in the division of oncology and therapeutics research at the City of Hope Cancer Center in Duarte. “Then there’s a little bit of a reality check.”

Nearly two dozen anti-angiogenesis drugs are in trials right now -- some of them natural, others cooked up in labs -- including such surprising compounds as thalidomide, responsible for birth defects when prescribed for pregnant women in the 1950s; Celebrex, the anti-arthritis drug; and squalamine, a chemical extracted from the cartilage of sharks.

And recent reports have been promising. Last month, at a cancer meeting in Frankfurt, French scientists reported that a drug developed by Sugen Inc. shrank tumors by 50% or more in a quarter of the 23 patients treated, and that it stabilized tumor size in five others. All of the patients in this early, phase I, trial had advanced cancers that no longer responded to other therapies.

Another drug, Avastin, developed by Genentech Inc., more than doubled the time to disease progression in 116 patients with advanced kidney cancer in an early trial reported in May, though in most patients it didn’t shrink the size of the tumors. Avastin also slowed progression in small studies for cancers of the colon, lung and breast and is currently in larger trials for those cancers.

But scientists are rightly cautious. Avastin, for instance, failed to show increased survival or delayed disease progression in a large breast cancer study reported in September, in spite of the fact that many tumors significantly shrank.

And even if trials pan out, we shouldn’t expect any miracles from anti-angiogenesis, scientists say -- just some useful drugs that work well for some cancers, under some circumstances, likely in partnership with other treatments.

The idea behind anti-angiogenesis was born largely from the persistence of one scientist, Dr. Judah Folkman, director of the Surgical Research Laboratories at Children’s Hospital Boston. Folkman had long been convinced that, to grow past a certain size, a tumor needed to orchestrate the growth of hundreds of tiny, hair-like blood vessels to supply itself with energy and oxygen.

“The clearest analogy is if you have 10 houses in a block and now you’re going to build 50 more on the same block, they just can’t exist on the same water supply -- you’ve got to put in more pipes,” Folkman said.

Folkman also proposed that doctors might be able to fight a cancer by figuring out a way to interfere with that process. And that would hold a big attraction for cancer research. Cancer cells are constantly mutating and changing and often become resistant to the drugs used to fight them. But the DNA of blood vessel cells is genetically stable, holding out hope that a drug aimed at them would work for much longer.

For years, Folkman’s ideas were dismissed by his colleagues, who thought that already existing blood vessels would more than satisfy a tumor’s needs. But Folkman turned out to be right.

Today, scientists know a lot about how tumors take advantage of the body’s system for forming our complex mesh of veins and arteries -- and by doing so, manage to grow large and threaten life. The cancer cells ooze “come hither” chemicals into the surrounding tissue; these chemicals find their way to blood vessel cells and trigger fresh growth toward the tumor.

Scientists have also found chemicals that block that blood vessel growth. One, called angiostatin, was heroically purified from hundreds of liters of mouse urine by Folkman’s research associate, Dr. Michael O’Reilly, in 1993. Another, endostatin, was extracted by the same group from cell culture medium, in 1997.

These drugs certainly looked potent in some animal experiments. In one study, for instance, angiostatin reduced the rate of tumor spread in mice by a factor of 20.

But it was in 1998 that the frenzy came, after an article in the New York Times quoted a Nobel Prize-winning scientist saying that Folkman would cure cancer “in two years.” Phones rang off the hook in cancer centers across the country.

That climate set the stage for disappointment when early clinical trials for endostatin and angiostatin were reported in 2001: The drugs appeared safe and showed slight signs of clinical benefit, but no more than that.

Folkman points out that these were very early studies, “phase I” trials that are not designed to study effectiveness, just safety. He says endostatin and angiostatin, which are still in trials, are showing increasing benefit as patients stay on them longer.

But should they fail, they won’t be alone: Other anti-angiogenesis drugs have fallen by the wayside in recent years.

“I think it’s fair to say that all the novel approaches to cancer treatment, including anti-angiogenesis, are turning out to be as complicated to develop clinically as we expected,” says Dr. Louise Grochow, chief of the investigational drug branch at the National Cancer Institute.

Yet with each failure comes new knowledge -- and important course corrections.

Scientists now know, for instance, that there is more than one way to lure growth of a blood vessel: If the drug doesn’t block the particular method a tumor is using, that drug won’t help shrink the tumor.

Thus, oncologists must learn to better target their therapies, just as doctors today give tamoxifen or Herceptin only to patients with specific kinds of breast cancer.

And, the tumor can play wily tricks. Block one angiogenesis pathway and -- sooner or later -- one of the cancer cells will mutate to draw in blood vessels a new way.

Thus, a multi-pronged approach makes sense: one in which several angiogenesis pathways are wiped out together.

The nature of both the Sugen drug (known as SU11248) and Avastin may be the reason they’ve done better than some of the others. SU11248 blocks several chemicals involved in blood vessel growth.

Avastin is an antibody that binds to, and hamstrings, a protein called VEGF -- which is involved in multiple blood vessel-forming pathways.

In the end, researchers believe that anti-angiogenesis may turn out to be not the answer to cancer, but part of the answer. They envision the battle taking place on multiple fronts: attacking tumors directly (with traditional chemotherapy and radiation as well as tailor-made drugs such as Herceptin) and also cutting off the tumors’ blood supply -- much as soldiers fire missiles at enemy forces and also blow up bridges to cut off supply lines.

Some scientists say that the anti-angiogenesis approach moved too fast into clinical trials before the complex biology of blood-vessel growth had been adequately figured out.

“You may have an idea that, ‘This should be a target’ or ‘The biology should act this way,’ but if you don’t really know how things are acting, you might be wrong,” said Zena Werb, a professor of anatomy at UC San Francisco and a specialist on blood vessel growth.

But other scientists say that there’s nothing necessarily premature about the clinical work. Rather, what we’re seeing with anti-angiogenesis is simply cancer research as usual, complete with the requisite sea of cured mice and a high rate of clinical disappointment.

“This field is kind of littered with molecules that showed promise in the lab but failed to deliver in the clinic,” said Dr. Fairooz Kabbinavar, associate professor of medicine at UCLA’s Johnson Comprehensive Cancer Center. “Anti-angiogenesis research is really in its infancy, but I personally feel that it is here to stay. We have to learn how best to use it. We need to give it more time.”