Treatment with the antipsychotic drug perphenazine (bottom) caused malignant tumor cells to self-destruct in zebrafish engineered to have T-cell acute lymphoblastic leukemia. (Source: Harvard Medical School/The Journal of Clinical Investigation)A 50-year-old antipsychotic drug can combat a difficult-to-treat form of acute lymphoblastic leukemia (ALL) in zebrafish, according to new a study led by Harvard Medical School researchers. The drug, perphenazine, works by turning on a cancer-suppressing enzyme called PP2A and causing malignant tumor cells to self-destruct.
The study provides a prime example of finding new uses for older drugs. The findings also suggest that developing drugs that activate PP2A while avoiding perphenazine's psychotropic effects could help clinicians make much-needed headway against T-cell ALL and perhaps other tumors as well.
The results were published in the Journal of Clinical Investigation.
T-cell ALL, or T-ALL, is rarer and more aggressive than the B-cell form of ALL and has a relatively poor prognosis. Despite improvements in the treatments available, 20 percent of children and more than 50 percent of adults diagnosed with T-ALL succumb to it.
To identify possible new treatment options, a study team led by Alejandro Gutierrez and A. Thomas Look of Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Jon Aster of Dana-Farber Cancer Institute and Brigham and Women's Hospital screened a library of 4,880 compounds—including FDA-approved drugs whose patents had expired, small molecules and natural products—in a zebrafish model of T-ALL.
Strategies that identify new uses for existing drugs have grown in popularity in recent years as a way of quickly developing new disease therapies. Zebrafish models are cost-effective platforms for rapidly conducting drug screens as well as basic stem cell, genetic, cancer and developmental research.
"We wanted to see if there were drugs or known bioactive molecules that are active against T-ALL that hadn't been tested yet," said Look, HMS professor of pediatrics at Dana-Farber. "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 phenothiazines, a family of antipsychotic medications that can block dopamine receptors.
The team verified perphenazine's anti-leukemic potential in vitro in several mouse and human T-ALL cell lines. Biochemical studies indicated that perphenazine's anti-tumor activity is independent of its psychotropic activity, and that it attacks T-ALL cells by turning on PP2A.
The fact that perphenazine works by reactivating a protein shut down in cancer cells is itself notable in the drug development field.
"We rarely find potential drug molecules that activate an enzyme," said Gutierrez, HMS assistant professor of pediatrics at Boston Children’s. "Most new drugs deactivate some protein or signal that the cancer cell requires to survive. But, here, perphenazine is restoring the activity of PP2A in the T-ALL cell."
The team is 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 perphenazine's psychiatric effects.
"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," said Look.
The researchers see future PP2A inhibitors not as magic bullets but as potentially important additions to the oncologist's arsenal when treating patients with T-ALL.
"T-ALL patients are often on the borderline between a long remission and a cure," Look said. "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."
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."
Date: January 14, 2013