Novel Treatment Inhibits Tumor Growth
Targeting PP2A enzyme shows promise treating lung cancer.
Scientists are always searching for novel ways to interfere with cancer cells to prevent proliferation and metastasis. Phosphate molecules that are used to turn proteins on and off have become common targets for cancer drugs.
"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 researcher Goutham Narla, MD, PhD.
The PP2A enzyme has the ability to turn proteins off by removing phosphate molecules that bind to them, according to a study published by the Journal of Clinical Investigation.
"This tumor suppressor is turned off in pretty much every major cancer,” Dr Narla said. “Its inactivation is essential for a normal cell to become a cancer cell.”
In an effort to reactivate tumor suppression, the authors aimed to discover molecules that target PP2A directly. A team of 45 researchers screened drug-like molecules for the potential to reactivate PP2A in lung cancer cells and prevent tumors in mice models.
The team created investigational drug molecules from FDA-approved drugs. They discovered 1 prototype drug that attaches to a subunit of the PP2A protein and can reactivate the enzyme, according to the study.
This is the first study to directly activate an enzyme that removes phosphate molecules via a small molecule, according to the authors.
"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,” Dr Narla said. “Our drug actually binds to and turns on PP2A."
Importantly, the investigational drug was also found to prevent lung cancer cells from proliferating in mouse models. The authors reported that mice administered the drug had less tumors and did not experience the side effects of other cancer drugs.
This treatment was observed to be comparable to current combination therapies that slow the progression of lung cancer, according to the study.
To further understand where the experimental drug binds to PP2A, the investigators developed cells with mutations at the binding site. These tumors were not observed to benefit from the drug, since it could not attach and reactivate the enzyme.
These findings confirm that the drug binds to PP2A at 2 amino acids within a subunit of the enzyme, which could aid drug development efforts, according to the study.
"This is the first example ever of a cancer drug that directly binds to and activates an enzyme that removes phosphate molecules,” Dr Narla said. “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.”
The authors noted that there are numerous papers linking PP2A in a majority of major cancers. If their findings are confirmed in future clinical trials, patients with cancer may have a treatment option that turns on tumor suppression, according to the study.
"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,” Dr Narla concluded. “Our initial clinical trials would be quite broad, and would include a number of diverse cancer patients, including patients with lung cancer.”