Using pre-clinical cell and animal models, scientists have discovered a novel small molecule that works to directly activate a tumor suppressor protein (PP2A) and prevent the formation of lung cancer tumors. They published their results in The Journal of Clinical Investigation.
Phosphate molecules, the molecular switches responsible for turning cellular proteins on and off, are common drug targets.
“All the drugs we currently have to treat our cancer patients target what we call kinases, which attach phosphate molecules to proteins. But equally important to this are the enzymes that take the phosphate off,” said Goutham Narla, MD, PhD, Pardee-Gerstacker Professor in Cancer Research, and associate professor, Case Western Reserve University School of Medicine; and member of the Case Comprehensive Cancer Center, Cleveland, Ohio.
But the enzyme PP2A can turn tumor proteins “off” via removal of the phosphate molecules attached to them.
“This tumor suppressor is turned off in pretty much every major cancer. Its inactivation is essential for a normal cell to become a cancer cell,” explained Dr. Narla.
Michael Ohlmeyer, PhD, associate professor, Icahn School of Medicine at Mount Sinai, New York, NY, created prototype drug molecules from FDA-approved medications, and Dr. Narla and a team of 45 researchers collaborated in screening them for their ability to reactivate PP2A in lung cancer cells and prevent lung cancer tumors from developing in mice. They sought to find molecules directly targeting PP2A and thus reactive its tumor suppressor properties.
They discovered one prototype drug that had the ability to attach to a subunit of the PP2A protein and activate the enzyme. This drug also prevented proliferation of lung cancer cells in laboratory models, including mouse models in which injected mice had fewer lung cancer tumors with no weight loss or behavioral abnormalities associated with other cancer medications.
In the mouse models, this prototype drug had comparable efficacy to currently available combination therapies that are now used to slow the progression of lung cancer.
“There are some 2,000 plus papers on the role of PP2A in cancer. Breast cancer, prostate cancer, lung cancer, brain cancer, childhood cancers, ovarian cancer, endometrial cancer, every major cancer involves the inactivation of this protein. Molecules that allow us to turn it back on, like the one in our study, have the potential to work in a broad range of cancer patients,” said Dr. Narla. “There are indirect ways that have been shown to get at these kinds of enzymes, but this is the first example of a direct activation of one. Our drug actually binds to and turns on PP2A.”
These researchers also developed lung cancer cells with specific mutations at the putative drug binding site to confirm where the drug attaches to PP2A. They observed no benefit from treatment in mice carrying tumors that were created from the mutated cancer cells in that the drug could not attach to and reactivate PP2A. Thus, they confirmed that this prototype drug attaches to PP2A at two specific amino acids within the enzyme subunit.
“This is the first example ever of a cancer drug that directly binds to and activates an enzyme that removes phosphate molecules. Therefore our findings could have broad applicability to the treatment of a large number of human cancers, including lung cancer as we demonstrated in this paper,” said Dr. Narla.
“We are continuing to test our drug in a large series of animal models. If things continue to go well, we hope to start clinical trials next year with this drug. Our initial clinical trials would be quite broad, and would include a number of diverse cancer patients, including patients with lung cancer,” he concluded.
The study was funded by the National Institutes of Health (NIH), Howard Hughes Medical Institute (HHMI), Case Western Reserve University (CWRU), University Hospitals through the Harrington Discovery Institute, and Dual Therapeutics. The Icahn School of Medicine at Mount Sinai on behalf of the authors GN, MO, NSD, DBK have filed patents covering composition of matter on the small molecules used in the study for the treatment of human cancer and other diseases. Dual Therapeutics, LLC has licensed this intellectual property for the clinical and commercial development of this series of small molecule PP2A activators.