New Screening Could Lead to More Potent Cancer Drugs

Researchers have discovered a way to identify drugs that can specifically attack and kill cancer stem cells, a finding that could lead to a new generation of anticancer drugs and a new strategy of treatment.

Many researchers believe that tumor growth is driven by cancerous stem cells that, for reasons not yet understood, are highly resistant to standard treatments. Chemotherapy agents may kill off 99 percent of the cells in a tumor, but the stem cells that remain can make the cancer recur, the theory holds. Stem cells, unlike mature cells, can constantly renew themselves.

A practical test of this theory has been difficult because cancer stem cells are hard to recognize and have so far proved elusive targets. But a team at the Broad Institute, a Harvard-M.I.T. collaborative for genomics research, has devised a way of screening for drugs that attack cancer stem cells but leave ordinary cells unharmed.

The Broad team, lead by Piyush B. Gupta, screened some 16,000 chemicals, including all known chemotherapeutic agents approved by the F.D.A. The team reports in Thursday’s issue of Cellthat 32 of the chemicals selectively targeted cancer stem cells. These particular chemicals may or may not make good drugs, but the screening system proves for the first time, the researchers say, that it is possible to target cancer stem cells with drugs that leave ordinary cells alone. Only one of the 32 chemicals is approved as a drug for cancer..

Another approach to targeting cancer stem cells, based on the use of antibodies, was reported this month by OncoMed Pharmaceuticals, a company founded by Michael F. Clarke, a Stanford researcher who in 2003 discovered cancer stem cells in breast tumors.

If effective drugs against cancer stem cells can be developed, one obvious strategy would be to use them in combination with standard chemotherapeutic agents, so that all types of cells in a tumor could be attacked. In that way, cancer would be attacked as AIDS now is, with a cocktail of chemicals that blocks all escape paths. Both the AIDS virus and cancer cells can change their DNA to dodge an effective drug, but are thought to perish if confronted with many drugs at the same time.

Standard chemotherapy is often effective because the chemicals are applied in such large doses that they kill all cells. But this scorched-earth policy is stressful for the patient.

“You could probably lower the doses considerably with a combination of drugs that attached specific types of cell,” Dr. Gupta said.

Eric S. Lander, director of the Broad Institute, said: “If we make a drug that kills 99.9 percent of the cells in a tumor but fails to kill the 0.1 percent, that is the real problem. It’s a pyrrhic victory.”

Mr. Lander said that, given the new drug screening system and the idea of using combinations of drugs against cancer, “there is a potential for a real renaissance in cancer therapeutics.”

“We have not been able to do that yet with cancer,” he said, “but, if we could, it’s a numbers game, and we win.”

The cancer stem cell theory has been thrust into the spotlight in the last five years with the discovery of stem cells in many different types of solid tumors, including those of the breast, brain, prostate, colon and pancreas. This month, a Stanford team led by Irving Weissman reported finding the stem cells of bladder cancer.

But the theory is not without critics.

“The cancer stem cell hypothesis has in the past year been challenged on many fronts,” said Bert Vogelstein, a leading cancer geneticist at Johns Hopkins University. “For example, a paper on melanomas last year showed that 100 percent of melanoma cancer cells were cancer stem cells.”

If many of a tumor’s cells are stem cells, then existing chemotherapy agents are clearly killing them, Dr. Vogelstein said, and the cancer stem cell theory is not an effective guide to finding new drugs.

The theory has also aroused opposition because, in its extreme version, it implies that standard chemotherapy goes after the wrong targets and is ineffective.

“It’s the most amazing polarity that I’ve seen,” Dr. Clarke said of the debate over stem cells among cancer researchers. “It’s like two religions fighting.”

Some advocates of the idea believe that to dissolve tumors, it would be necessary only to target cancer stem cells, if such drugs existed. But the Broad Institute team and others take the view that a combination of drugs attacking each of the different types of cells in a tumor would be the best strategy.

One reason for using a combination of drugs is the suspicion that mature cancer cells may be able to convert themselves back into stem cells, a route that is apparently prohibited to normal mature cells.

“The possibility is that the nonstem cells in a tumor may regenerate de novo new stem cells,” said Robert Weinberg, a leading cancer biologist at M.I.T. and, with Dr. Lander, a co-author of the Cell report. “If one had ways of treating both the stem cells and the nonstem cells, then the de novo generation of stem cells would be dealt with.”

The basic insight of the cancer stem cell theory is that there is a hierarchy of cells in a tumor, with the stem cells at the top generating the mature cells that are the majority. Most researchers accept that this is good description of leukemias because Gleevec, a highly effective drug for chronic myelogenous leukemia, does not kill the stem cells, and the leukemia returns if the treatment is stopped.

But with solid tumors, “the jury is out,” Dr. Vogelstein said. If stem cells are very common in solid tumors, not just a small resistant reservoir of cells, “then there’s no difference between the stem cells and the bulk cancer — so a screen for drugs to kill melanoma cells is by definition also going to kill the melanoma’s cancer stem cells.”

Still, in Dr. Vogelstein’s view, the Broad Institute’s new screening method is important whether or not the cancer stem cell theory is correct. “Because most of the compounds in use now clearly aren’t doing the job we’d all like,” he said, “then novel methods for screening could be extremely valuable.”

The Broad Institute researchers hope that pharmaceutical companies will use their screening method to begin the long road to develop drugs against cancer stem cells.