As doctors and researchers explore the effectiveness of treating cancer patients with combinations of chemotherapy drugs, their attention has largely been focused on how much of each drug to give.

A new study has found that achieving best results may also require looking into how much time should pass between delivering one drug and the next.




Researchers led by members of the Department of Systems Biology at Harvard Medical School had been studying how silencing MDMX, an oncogene, affected the dynamics of p53, a natural tumor suppressor, in cancer cells when they realized those dynamics might affect the cells’ sensitivity to a second, chemotherapy-like treatment.

Live imaging of single cells revealed that time wildly affected cell survival. A short wait between disabling MDMX and administering chemotherapy made the two treatments synergistic, killing cancer cells more effectively than either would have alone, while a longer wait led to treatment resistance, allowing more cancer cells to withstand attack.

“This is the first time someone has shown that timing makes such a big difference in cells’ response to combination therapy,” said Galit Lahav, professor of systems biology at HMS and senior author of the paper, published March 10 in Science. “It’s a first look at how one treatment can change the internal state of individual cells to make them more or less sensitive to a second treatment.”

The findings indicate that testing combination treatments at only one time point, whether in lab experiments or clinical trials, may not tell the whole story.

“Right now, cancer clinical trials that use multiple drugs give them simultaneously,” said Sheng-hong Chen, a postdoctoral researcher in the Lahav lab and first author of the paper. “Our work shows that you need to understand the biology at the single-cell level to determine whether timing matters and to design an optimal schedule.”

The study also provides a new way to screen for small molecules that inhibit MDMX.

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