Washington D.C.: According to previous researches, anti-malaria drugs known as chloroquines were repurposed to treat cancer for decades, but until now no one knew exactly what the chloroquines were targeting when they attack a tumor.
Now, researchers from the University of Pennsylvania explained that an enzyme called PPT1 – opens up a new pathway for potential cancer treatments. The findings appeared in the Journal of Cancer Discovery.
The team also used CRISPR/Cas9 gene editing to remove PPT1 from cancer cells in the lab and found that eliminating it slows tumor growth. They detailed a potent chloroquine, known as DC661, that can take advantage of this new treatment pathway.
“The discovery of this target is critical because chloroquines are currently being evaluated in clinical trials all over the world, and this knowledge fundamentally changes the way we look at those trials,” said the study’s co-senior author Ravi K. Amaravadi.
PPT1 is an enzyme which helps in controlling both the mechanistic target of rapamycin (mTOR), a major regulator of growth in cancer cells, as well as a process called autophagy, a built-in resistance mechanism which allows cells to survive when under attack by breaking down unneeded parts and recycling them to stay alive.
In a previous study, Penn researchers showed these two processes work hand-in-hand, as autophagy provides the nutrients that allow mTOR to direct growth, while mTOR shuts off autophagy when the nutrients aren’t needed. Building off their previous work, researchers used CRISPR/Cas9 to knockout PPT1 from cancer cells to see if its removal had the same effect as a chloroquine.
Researchers further proved that the concept by targeting melanoma cells with DC661, which specifically targets PPT1 and produces cell death in many cell lines tested both in vitro and in vivo.
It is a dimeric form of the antimalarial drug quinacrine – meaning it has two molecules of quinacrine bound together with a special linker. Amaravadi added that when you put the pieces together, it shows incredible promise.
“We now have a specific molecular target in cancer, as well as a potent way to reach it,” Amaravadi said.
“It not only provides a new context for current clinical trials involving hydroxychloroquine but also, with further development of these compounds toward clinical drug candidates, it opens the door for head-to-head testing of our compounds or their optimized derivatives versus current chloroquines to see which is more effective.”