Treatment Can Make Cancer Stronger

What doesn't kill cancer cells makes them stronger, Duke researchers have observed.

Doctors use radiation and chemotherapy to destroy cancer cells. About half of patients are cured -- that is, all of their tumor cells die.

The other half of the time, some tumor cells survive treatment. These cancer cells are more aggressive than they were before treatment, says Mark W. Dewhirst, DVM, PhD, professor of radiation oncology at Duke University.

"When you give a tumor treatment, whatever cells survive are going to be more resistant to that treatment," Dewhirst tells WebMD. "Those not killed are healthier cancer cells."

This does not mean radiation and chemotherapy don't work. It does mean that additional new treatments will be needed. And to know what treatments will work best, Dewhirst says doctors need to know how cancer cells survive radiation and chemotherapy.

The key may be a protein called HIF -- hypoxia-inducing factor. Government, university, and drug-company researchers are racing to develop new drugs that inhibit HIF. But patients may not have to wait that long: Existing drugs, already approved by the FDA for cancer treatment, turn out to be potent anti-HIF agents.

Why is HIF suddenly a big deal? It's the key to a different way of looking at cancers.

A 'New' Theory of Cancer

It's been known for about 50 years that solid tumors have areas that don't get much blood -- and that cells in these areas survive without much oxygen.

For a long time, this was thought to be an interesting curiosity. But now the ability of cancer cells to survive without oxygen -- to become hypoxic -- is being seen as a driver of cancer progression.

"A cancer cell that doesn't get much oxygen is like a rat deserting a sinking ship," Dewhirst says. "It will do things to try to help itself."

So the cell does four things:

• It sends out a signal for help, asking the body to grow more blood vessels in the tumor.


• It changes the way it eats , switching from oxygen metabolism to anaerobic metabolism.


• It prepares itself for the day it gets help, building defenses against a burst of oxygen molecules that is toxic to anaerobic cells.


• And the cell is going to try to get out of there -- to invade a blood vessel and go somewhere else in the body to grow.

• New blood vessels let the tumor grow larger.


• Cells that don't use oxygen are much less sensitive to chemotherapy and radiation.


• Cells resistant to bursts of oxygen (oxidative stress) also are resistant to some of the ways the body gets rid of cancer cells.


• Cells that wander spread cancer to distant parts of the body.

Part of that revolution has been Semenza's discovery (also made independently by Oxford researcher Peter Ratcliffe, MD) of HIF-1. HIF-1 is the signal that transforms a cell from an oxygen-using cell to an anaerobic cell.

HIF: Key to Cancer Treatment Success?

"It's been shown that in a variety of different cancer types, those with most HIF-1 have the worst outcome," Semenza tells WebMD. "The basis for this is the fact that HIF-1 controls the expression of hundreds of genes that play critical roles in cancer biology."

One of the first researchers to start looking for drugs that target HIF-1 is oncologist Giovanni Melillo, MD, of the U.S. National Cancer Institute (NCI). After screening hundreds of compounds for anti-HIF activity, Melillo and colleagues made a surprising discovery: A number of existing cancer chemotherapies turn out to inhibit HIF.

The most potent, Melillo says, is a rug called topotecan, marketed under the brand name Hycamtin. It's already approved by the FDA as a second-line treatment for ovarian and small-cell lung cancers. So why isn't this drug already revolutionizing cancer treatment?

"The key to this treatment is the dose," Melillo tells WebMD. "For chemotherapy, one usually gives the maximum tolerated dose. And the timing is important, because when topotecan is used as chemotherapy one needs to let the patient recover from toxicity. We propose to give lower doses of topotecan daily to achieve this effect on HIF-1 in a nontoxic fashion."

Indeed, in an NCI clinical trial, Melillo and colleagues found that topotecan given this way does not have the toxic effects seen when the drug is used in massive doses as a chemotherapy.

But if cancer researchers have learned one thing, it is that no single type of treatment is going to cure cancer.

"Successful treatment of tuberculosis requires the administration of three antibiotics; successful treatment of AIDS requires the administration of three antiviral agents," Semenza recently wrote. "It is not reasonable to expect that the successful treatment of cancer can be accomplished reliably with any fewer than three anticancer agents."

Semenza, Dewhirst, and Melillo agree that HIF-1 inhibitors will have major effects only when combined with other agents.

Dewhirst proposes using such inhibitors along with radiation and chemotherapy. Melillo and Semenza are excited about using the drugs with angiogenesis inhibitors, such as Avastin, which prevent tumors from growing new blood vessels.

Melillo's team is planning a clinical trial testing Avastin in combination with topotecan. And Dewhirst and colleagues have just completed an early safety study of another HIF-1 inhibitor, ENMD-1198 from EntreMed Inc. (Dewhirst has no financial interest in the company).

"HIF-1 inhibition is a very exciting opportunity for cancer treatment," Dewhirst says.

By Daniel DeNoon
Reviewed by Louise Chang
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