In a prime example of finding new uses for older drugs, studies in zebrafish show that a 50-year-old antipsychotic medication called perphenazine can actively combat the cells of a difficult-to-treat form of acute lymphoblastic leukemia (ALL). The drug works by turning on a cancer-suppressing enzyme called PP2A and causes malignant tumor cells to self-destruct.
The findings suggest that developing medications that activate PP2A, while avoiding the psychotropic effects of perphenazine, could help clinicians make much-needed headway against T-cell ALL (T-ALL), and perhaps other tumors as well.
The study was led by A. Thomas Look, MD, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, and reported the in the Journal of Clinical Investigation (2014; doi:10.1172/JCI65093).
T-ALL is rarer and more aggressive than the B-cell form of ALL, and it has a relatively poor prognosis. Despite improvements in the treatments available, 20% of children and more than 50% of adults diagnosed with T-ALL succumb to it.
To identify possible new treatment options, the research team screened a library of 4,880 compounds—including FDA-approved drugs whose patents had expired, small molecules, and natural products—in a model of T-ALL engineered using zebrafish.
“We wanted to see if there were drugs or known bioactive molecules that are active against T-ALL that hadn’t been tested yet,” Look explained. “There may be drugs available for other indications that could be readily repurposed if we can show activity.”
One of the strongest hits in the zebrafish screen was the drug perphenazine. It is a member of the phenothiazine family of antipsychotic medications, which have been used for 50 years because of their ability to block dopamine receptors.
The team verified perphenazine’s antileukemic potential in vitro in several mouse and human T-ALL cell lines. Biochemical studies indicated that perphenazine’s antitumor activity is independent of its psychotropic activity, and that it attacks T-ALL cells by turning on PP2A.
The researchers are now working to better understand the interactions between PP2A and perphenazine. They also want to search for or develop molecules that bind to and activate the enzyme more tightly and specifically to avoid the psychiatric effects of perphenazine.
“The challenge is to use medicinal chemistry to develop new PP2A inhibitors similar to perphenazine and the other phenothiazines, but to dial down dopamine interactions and accentuate those with PP2A,” Look said.
“T-ALL patients are often on the borderline between a long remission and a cure,” Look continued. “If we can push the leukemia cells a little harder, we may get more patients who are actually cured. In this way, PP2A inhibitors may, in combination with other drugs, make a real difference for patients.”
It may be that the benefits of PP2A-activating drugs could extend beyond T-ALL. “The proteins that PP2A suppresses, such as Myc and Akt, are involved in many tumors,” Look noted. “We are optimistic that PP2A activators will have quite broad activity against different kinds of cancer, and we’re anxious to study the pathway in other malignancies as well.”