Targeting Cancer Through Its Roots

By Ben Harder

Targeting Cancer Through Its Roots

What is angiogenesis and why are cancer researchers studying it?

By Ben Harder

Based on his observations, Folkman proposed in 1971 that blocking angiogenesis could stop cancer. “That hypothesis,” says tumor biologist Rakesh Jain of Massachusetts General Hospital and Harvard Medical School in Boston, “drove this entire field.” Since then, cancer researchers have proven the core principle of Folkman’s idea.

More than half the tumors that make the angiogenic switch produce a molecule called vascular endothelial growth factor, or VEGF. The rest rely on some other molecule that performs a similar function. These so-called angiogenic factors trick normal endothelial cells, which line all blood vessels, into forming new vessels just where the tumor needs them.

Molecules that inhibit angiogenesis do so either by interfering with the biological activity of angiogenic factors or by restraining endothelial cells from moving or dividing.

The body naturally produces at least 28 kinds of angiogenesis inhibitors, without which, says Folkman, “we’d all have a lot more cancer.” Drugs such as Avastin—approved in 2004 to treat patients with metastatic colorectal cancer—mimic certain effects of some of these natural guardian molecules.

In addition to Avastin and the two other new compounds that counter angiogenesis, several previously approved drugs have similar properties that scientists recently discovered. Other experimental anti-angiogenic medicines are under development, and at least eight are being tested in clinical trials.

Studies show that angiogenesis inhibitors work best in combination with treatments such as radiation and chemotherapy. In fact, they seem to make those standard therapies more effective.

That makes sense, says Jain. A tumor’s blood vessels grow sloppily and tend to leak. “Abnormal vessels are not very efficient for delivering drugs and reduce the effectiveness of drugs by creating a hostile environment in tumors,” he says. “Anti-angiogenic therapy, before it destroys blood vessels, can make them close to normal.” Chemotherapy drugs given during this window—when a tumor’s blood vessels have a more normal structure—are likely to infiltrate a tumor more easily and tend to be more effective, he says.

Abnormal blood vessels also provide a poor supply of oxygen and other nutrients, making a tumor more “angry,” or aggressive, says Jain. But, he says, anti-angiogenic drugs can make a tumor less malignant and less likely to metastasize.

An important benefit, Folkman adds, is that anti-angiogenesis drugs generally cause “far fewer side effects than standard chemotherapy.”

“Most people do not feel physically unwell from bevacizumab and most other angiogenesis inhibitors,” agrees oncologist Herbert I. Hurwitz of Duke University Medical Center in Durham, N.C. “But,” he cautions, “this class of drugs may in fact increase the risk of vascular health problems,” such as heart attacks, in some patients.

Folkman stresses that angiogenesis inhibition is not a panacea for cancer. Avastin, for instance, is “a marvelous drug, but it is made to block only one angiogenesis protein,” he says.

That’s a drawback because tumors can learn to make about half a dozen different kinds of angiogenesis-promoting molecules. To stop cancer indefinitely, doctors might need to counter each of these angiogenic factors with a different inhibitor or use a “broad-spectrum” drug that simultaneously blocks several factors, he says.

Also, anti-angiogenic drugs have only been proven to prolong life in patients with advanced disease. But in such seriously ill people, the drugs don’t usually hold cancer at bay indefinitely.

However, Sledge says, treating patients with anti-angiogenic drugs early in the course of their illness “might prevent the cancer from ever coming back.” Trials designed to test that concept could begin this year, he says. CR endbox

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