MIT researchers have identified a critical defense mechanism that tumor cells employ to survive the toxic effects of chemotherapy--knowledge that could very soon lead to more effective cancer treatments.
The findings, reported as the cover story in the Feb. 13 issue of Cancer Cell, show that after chemotherapy, many tumors resort to using a signaling pathway normally associated with the inflammatory response in order to survive.
Drugs that knock out this inflammatory defense mechanism would render tumors vastly more susceptible to chemotherapy, according to Michael Yaffe, MIT associate professor of biology and biological engineering, and leader of the research team. One such drug is already in the pipeline.
"In the clinic, we could use lower doses of chemotherapy and get a more profound reduction of the tumor with fewer side effects in patients by targeting this pathway," said Yaffe, who is affiliated with MIT's Cancer for Cancer Research, the Broad Institute of MIT and Harvard, and Beth Israel Deaconess Medical Center.
Knocking out the inflammatory pathway should be an effective tactic against most tumors--namely, tumors that lack p53, a protein known to protect normal cells from becoming cancerous. (Cells with p53 don't rely on the pathway for survival.) Up to 80 percent of human tumors lack p53, making them susceptible to the new treatment.
The researchers knocked out the inflammatory pathway, called the MK2 pathway, in mouse tumors using a technique known as RNA interference. When they did so in conjunction with low doses of common chemotherapy agents, such as cisplatin, they saw a dramatic reduction in tumor size. "The tumors basically melted away," says Yaffe.
In contrast to the growing tumors, the normal cells were unaffected. So "targeting MK2 would preferentially sensitize only the tumor tissue to chemotherapy, and spare patients the side effects from damaging healthy non-tumor cells," explains Christian Reinhardt, a postdoctoral fellow in the Center for Cancer Research and first author of the study.
One such drug against the MK2 pathway is already in clinical trials. UCN-01, a compound identified in a NIH-sponsored screening of potential anti-tumor agents, is being tested against lymphoma and relapsed solid tumors. Some of the targets of UCN-01 are known, but until now, many of UCN-01's anti-tumor effects have not been explained.
Now that more of the mechanism behind UCN-01 is known, Yaffe hopes it will get more attention as a potential anti-cancer drug. He also hopes that researchers will try to identify other drugs that interfere with the same pathway.
Other authors on the paper are Aaron Aslanian, a postdoctoral fellow in the CCR, and Jacqueline Lees, professor of biology and associate director of the CCR.
The research is funded by the David H. Koch Fund and the National Institutes of Health.
A version of this article appeared in MIT Tech Talk on February 14, 2007 (download PDF).