Drugs that kill cancer stem cells identified
Finding could lead to new treatments
Stem cell killers: A team of researchers found certain chemicals that selectively attack cancer stem cells, thought to be the source of cancers.
Chemotherapy controversy: Some say the findings suggest that standard chemotherapy is ineffective because it goes after the wrong kinds of cells.
Combination approach: The researchers and others believe the best approach against cancer may be chemotherapy in addition to any new drugs that emerge based on the study's findings.
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 anti-cancer medicines 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, or spread to other tissues in the body to cause new cancers. Stem cells, unlike mature cells, can constantly renew themselves and are thought to be the source of cancers when, through mutations in their DNA, they throw off their natural restraints.
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-MIT collaborative for genomics research, has devised a way of screening for drugs that attack cancer stem cells but leave ordinary cells unharmed.
Cancer stem cells are hard to maintain in sufficient numbers, but the Broad Institute team devised a genetic manipulation to keep breast cancer stem cells trapped in the stem cell state.
The team, led by Dr. Piyush Gupta, screened about 16,000 chemicals, including all known chemotherapeutic agents approved by the Food and Drug Administration. The team reported in yesterday's issue of Cell that 32 of the chemicals selectively went after 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 single out 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 concentrating on cancer stem cells, based on the use of antibodies, was reported this month by OncoMed Pharmaceuticals, a company founded by Dr. Michael 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 is now — 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 approach is stressful for the patient.
“You could probably lower the doses considerably with a combination of drugs that attacked specific types of cell,” Gupta said.
Dr. Eric 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.”
Lander said that given the new drug screening system and the idea of using combinations of drugs against cancer, there was “a potential for a real renaissance in cancer therapeutics.”
“We have not been able to do that yet with cancer,” he added, “but if we could, it's a numbers game, and we win.”
The theory has also aroused opposition, however, 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,” Clarke, the Stanford researcher, 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 to go after only 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.