Timing is everything

A recent MIT study reveals that the timing and order of drug administration can significantly affect drug efficacy

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CAMBRIDGE, Mass.—Combination therapies have become one ofthe new standards in cancer care, due to their increased efficacy over singulardrugs, but a recent study by researchers at the Massachusetts Institute ofTechnology (MIT) has revealed that the timing of combination therapies mightbolster their effectiveness even further. The team discovered that staggeringthe administration of two cancer drugs significantly increased their ability todestroy breast cancer cells.
The study was led by Michael Yaffe, the David H. KochProfessor of Biology and Biological Engineering at MIT, and postdoctoralstudent Michael Lee, lead author of the paper. They focused on a class ofbreast cancer cells known as triple negative, cells without overactiveestrogen, progesterone or HER2 receptors. Triple-negative tumors representroughly 16 percent of breast cancer cases and tend to be much more aggressive thanother types.
Yaffe has studied the cell-signaling pathways responsiblefor controlling cell behavior for years, pathways that go berserk in cancercells and lead to uncontrolled growth in the absence of stimuli and a sort ofimmunity to the cell signals that should trigger apoptosis. Yaffe's interestled to the idea that drug-induced changes in the signaling pathways, ifstaggered in terms of timing, might be capable of altering cancer cells to aless malignant state.
Yaffe and Lee thought that by administering a drug thatshuts down one of the pathways that promotes uncontrolled growth in cancercells, it might be possible to sensitize those cells to DNA-damaging drugs, ahypothesis they tested through combinations of 10 DNA-damaging drugs and adozen drugs that inhibit different pathways, all with different timingschedules.
"Our previous systems-biology work had primed us to the ideathat you could potentially drive a cell from a state in which only a fractionof the tumor cells were responsive to chemotherapy into a state where many moreof them were responsive by therapeutically rewiring their signaling networks ina very time-dependent way," Yaffe noted in a press release.
"We thought we would retest a series of drugs that everyoneelse had already tested, but we would put in wrinkles—like time delays—that, for biological reasons, we thought were important," Lee added. "I thinkhad it not worked, we would have gotten a lot of pushback, but we were prettyconvinced that there was a lot of information being left on the table byeveryone else."
The combination that worked the best consisted of apretreatment of erlotinib followed by doxorubicin, both of which have alreadysecured regulatory approval. Erlotinib is approved for the treatment of pancreatic cancerand some types of lung cancer, and works by inhibiting a protein called theepidermal growth factor (EGF) receptor, which is found on the surface of cells.When the EGF receptor is constantly active, which is common in many cancercells, it stimulates a signaling pathway that promotes the excessive growth anddivision typical of cancer. Pretreatment with erlotinib affected approximately2,000 genes and shut down pathways responsible for excessive growth. The studyrevealed that by administering erlotinib between four and 48 hours beforedoxorubicin, cell death significantly increased, with the staggered doseskilling up to 50 percent of triple-negative cells compared to the 20 percentkilled in normal simultaneous administration. The same results were not seen ifthe order of administration was switched, however.
The treatment proved effective not only in lab-grown cellsbut also in mice with tumors, as the tumors both shrank and did not grow backfor the two-week duration of the study. Similar results were also seen in thetreatment of HER2-positive breast cancer cells and some types of lung cancer.When the mice were tested with chemotherapy or simultaneous administration ofthe 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 ofefficacy has been universally true. It's just a matter of finding the rightcombinations," said Lee.
To take the results further, the MIT team has joined up withresearchers at the Dana-Farber Cancer Institute to begin planning clinicaltrials for the staggered drug therapy.
The paper, "Sequential application of anticancer drugsenhances cell death by rewiring apoptotic signaling networks," appeared in theMay 11 edition of Cell. Additionalauthors include Albert S. Ye, Alexandra K. Gardino, Anne Margriet Heijink,Peter K. Sorger and Gavin MacBeath. The study was funded by the NationalInstitutes of Health Integrative Cancer Biology Program and the Department ofDefense.

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