20 November 2018
There are currently about 20 clinical trials underway evaluating a class of malaria drugs known as chloroquines in several tumor types, including breast cancer, lung cancer and multiple solid tumors, according to ClinicalTrials.gov. Anti-malarial drugs, in fact, have long been of interest in the oncology community because of their ability to shrink some cancers.
But why do chloroquines have that power? Researchers at the University of Pennsylvania believe they’ve figured out precisely what chloroquines are targeting when they attack tumors.
Researchers at Penn’s Abramson Cancer Center discovered that the antimalarial drugs target the enzyme PPT1, which in turn controls rapamycin (mTOR). This is important insight, because mTOR regulates both the growth of cancer cells and a process called “autophagy,” whereby cells recycle components in order to survive when they’re facing an attack.
The Penn team made the discovery by first using the CRISPR-Cas9 gene editing technology to remove PPT1 from cancer cells. That slowed tumor growth. Then they took a chloroquine that was developed at Penn called DC661 and aimed it at melanoma cells. That confirmed their hunch that PPT1 is the pathway chloroquines are targeting, they reported in the journal Cancer Discovery.
“The edited cells look like they've been treated with a drug, and they grow significantly slower than the unedited cells,” said co-senior author Ravi Amaravadi, M.D., an associate professor of hematology-oncology, in a statement. “We also compiled data from existing databases and found PPT1 is both highly expressed in most cancers and also associated with poor outcomes.”
DC661 is an engineered form of the malaria treatment quinacrine. Penn scientists created a “dimeric” form of the drug by linking two molecules together. They believe this special formulation of quinacrine will prove more potent than the monomeric antimalarial drugs currently in clinical trials—and they have early evidence in mice that’s promising, they reported.
Drugs that inhibit mTOR are already being used to treat a variety of tumor types, including breast, brain and kidney cancers, but their effectiveness has been limited. Most recently, AstraZeneca dropped its mTOR inhibitor vistusertib from its pipeline, after having reported mixed results from trials of the drug in several tumor types.
Penn’s Amaravadi has co-founded a startup called Pinpoint Therapeutics to further develop antimalarial derivatives to treat cancer. He is working with Jeffrey Winkler, a professor of chemistry at Penn, who was also a co-senior author of the new study. They believe their latest research “opens the door for head-to-head testing of our compounds or their optimized derivatives versus current chloroquines to see which is more effective,” Amaravadi said.Print
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