With increased regulations on pharmaceutical companies, billion-dollar research that will fail 95 percent of the time and a short window to sell successful products before genetic versions and lawsuits take the revenue away, the future might be the past: it's a lot smarter to find new uses for old drugs than risk developing new ones.
A group of researchers recently did just that, discovering 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), a fast-growing cancer of a type of white blood cells called lymphocytes. The drug works by turning on a cancer-suppressing enzyme called PP2A and causing malignant tumor cells to self-destruct.
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 percent of children and more than 50 percent of adults diagnosed with T-ALL succumb to it. To identify possible new treatment options, the collaborators 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.
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 used for 50 years, because they 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 findings suggest that developing medications 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 fact that perphenazine works by reactivating a protein shut down in cancer cells is itself novel in the drug development field.
"We rarely find potential drug molecules that activate an enzyme," says Alejandro Gutierrez, MD, of Dana-Farber/Boston Children's Cancer and Blood Disorders Center. "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 A. Thomas Look, MD, also of Dana-Farber/Boston Children's Cancer and Blood Disorders Center.
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."
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."