Anti-malaria drugs known as chloroquines have been 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 Abramson Cancer Center say they have identified that target—an enzyme called PPT1—opening up a new pathway for potential cancer treatments. 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 developed at Penn, known as DC661, which can take advantage of this new treatment pathway. Their findings are published in Cancer Discovery.
“The discovery of this target is critical because chloroquines are currently being evaluated in clinical trials all over the world, including here at Penn, and this knowledge fundamentally changes the way we look at those trials,” says the study’s co-senior author Ravi K. Amaravadi, an associate professor of Hematology-Oncology in the Perelman School of Medicine. Jeffrey D. Winkler, the Merriam Professor of Chemistry in the School of Arts and Sciences, was the other co-senior author.
PPT1 is an enzyme that controls 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 that allows cells to survive when under attack by breaking down unneeded parts and recycling them to stay alive.
“The edited cells look like they’ve been treated with a drug, and they grow significantly slower than the unedited cells,” Amaravadi says. “We also compiled data from existing databases and found PPT1 is both highly expressed in most cancers and also associated with poor outcomes.”
Read more at Penn Medicine News.
