Timing is everything
by Kelsey Kaustinen  |  Email the author


CAMBRIDGE, Mass.—Combination therapies have become one of the new standards in cancer care, due to their increased efficacy over singular drugs, but a recent study by researchers at the Massachusetts Institute of Technology (MIT) has revealed that the timing of combination therapies might bolster their effectiveness even further. The team discovered that staggering the administration of two cancer drugs significantly increased their ability to destroy breast cancer cells.  
The study was led by Michael Yaffe, the David H. Koch Professor of Biology and Biological Engineering at MIT, and postdoctoral student Michael Lee, lead author of the paper. They focused on a class of breast cancer cells known as triple negative, cells without overactive estrogen, progesterone or HER2 receptors. Triple-negative tumors represent roughly 16 percent of breast cancer cases and tend to be much more aggressive than other types.  
Yaffe has studied the cell-signaling pathways responsible for controlling cell behavior for years, pathways that go berserk in cancer cells and lead to uncontrolled growth in the absence of stimuli and a sort of immunity to the cell signals that should trigger apoptosis. Yaffe 's interest led to the idea that drug-induced changes in the signaling pathways, if staggered in terms of timing, might be capable of altering cancer cells to a less malignant state.  
Yaffe and Lee thought that by administering a drug that shuts down one of the pathways that promotes uncontrolled growth in cancer cells, it might be possible to sensitize those cells to DNA-damaging drugs, a hypothesis they tested through combinations of 10 DNA-damaging drugs and a dozen drugs that inhibit different pathways, all with different timing schedules.  
"Our previous systems-biology work had primed us to the idea that you could potentially drive a cell from a state in which only a fraction of the tumor cells were responsive to chemotherapy into a state where many more of them were responsive by therapeutically rewiring their signaling networks in a very time-dependent way," Yaffe noted in a press release.  
"We thought we would retest a series of drugs that everyone else had already tested, but we would put in wrinkles —like time delays—that, for biological reasons, we thought were important," Lee added. "I think had it not worked, we would have gotten a lot of pushback, but we were pretty convinced that there was a lot of information being left on the table by everyone else."  
The combination that worked the best consisted of a pretreatment of erlotinib followed by doxorubicin, both of which have already secured regulatory approval. Erlotinib is approved for the treatment of pancreatic cancer and some types of lung cancer, and works by inhibiting a protein called the epidermal growth factor (EGF) receptor, which is found on the surface of cells. When the EGF receptor is constantly active, which is common in many cancer cells, it stimulates a signaling pathway that promotes the excessive growth and division typical of cancer. Pretreatment with erlotinib affected approximately 2,000 genes and shut down pathways responsible for excessive growth. The study revealed that by administering erlotinib between four and 48 hours before doxorubicin, cell death significantly increased, with the staggered doses killing up to 50 percent of triple-negative cells compared to the 20 percent killed in normal simultaneous administration. The same results were not seen if the order of administration was switched, however.  
The treatment proved effective not only in lab-grown cells but also in mice with tumors, as the tumors both shrank and did not grow back for the two-week duration of the study. Similar results were also seen in the treatment of HER2-positive breast cancer cells and some types of lung cancer. When the mice were tested with chemotherapy or simultaneous administration of the two drugs, however, the tumors shrank initially but grew back later.  
"The drugs are going to be different for each cancer case, but the concept that time-staggered inhibition will be a strong determinant of efficacy has been universally true. It's just a matter of finding the right combinations," said Lee.  
To take the results further, the MIT team has joined up with researchers at the Dana-Farber Cancer Institute to begin planning clinical trials for the staggered drug therapy.  
The paper, "Sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks," appeared in the May 11 edition of Cell. Additional authors include Albert S. Ye, Alexandra K. Gardino, Anne Margriet Heijink, Peter K. Sorger and Gavin MacBeath. The study was funded by the National Institutes of Health Integrative Cancer Biology Program and the Department of Defense.
Code: E05231204

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