A huge range of drugs are in development to help fight cancer, but sometimes they work better in pairs than alone. Now researchers at MIT have identified a surprising new dynamic drug duo, combining two classes that are already beginning to be widely used. Interestingly, the combo appears to work in a completely different way to what scientists previously expected.
The researchers started with a class of drugs called PLK1 inhibitors, which have proven effective in the past and are beginning to be tested in phase 2 clinical trials. The team set out to boost the effects of this type of drug, to see if it could be made even more effective.
PLK1 inhibitors primarily work by messing with mitosis, the process cancer cells use to divide and spread quickly. But as a side effect, they can also cause oxidative damage to cells – and this is the area the team wanted to give a leg up to. The researchers reasoned that PLK1 inhibitors could be even more potent a cancer-killer if they paired them up with another drug that prevents cells from repairing oxidative damage.
A drug called TH588 fit the bill. So the team partnered them up and tested them on various types of cancer cells. And sure enough, the dynamic duo worked extremely well, with the researchers finding they could drastically reduce the amount of each drug needed. In some cases, by giving them together they were able to use just 10 percent of the original dose of each drug while still getting the same rate of cell death in the cancers.
"It's really striking," says Brian Joughin, first author of the study. "It's more synergy than you generally see from a rationally designed combination."
But that's not the end of the story. On closer inspection, the team realized the potency of the pair wasn't due to oxidative damage at all. After running software analysis and conducting additional experiments the team found out that TH588 homes in on the exact same target as the PLK1 inhibitor – the mitotic spindle, a structure that forms as a cell prepares to divide.
"This combination that we found was very nonobvious," says Michael Yaffe, lead researcher on the study. "I would never have given two drugs that both targeted the same process and expected anything better than just additive effects."
There are a few benefits to the surprise discovery. Because the combo targets a process of cell division that only cancer uses, the treatment narrows in on tumors and leaves healthy cells alone. The two drugs are also fairly common, meaning clinical trials could appear sooner than with a drug developed from scratch. The team hopes that it might only take a year or two.
"This is a combination of one class of drugs that a lot of people are already using, with another type of drug that multiple companies have been developing," says Yaffe. "I think this opens up the possibility of rapid translation of these findings in patients."
On top of that, the analysis gave the team a better insight into how cancer cells divide, and unveiled some new potential drug targets to interrupt that process. In fact, existing drugs are already known to have some of those effects, but hadn't been applied to cancer treatments before.
The research was published in the journal Cell Systems.
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