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 causing malignant tumor cells to self-destruct.
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.
A study team led by Alejandro Gutierrez, MD, and A. Thomas Look, MD, of Dana-Farber/Boston Children's Cancer and Blood Disorders Center, and Jon Aster, MD, PhD, of Dana-Farber Cancer Institute and Brigham and Women's Hospital, reported the results Jan. 9 in the Journal of Clinical Investigation.
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, Gutierrez, Look and their 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.
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," 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 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 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," Gutierrez explained. "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."
Gutierrez and Look, along with their collaborators, 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 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," Look said.
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."
This study was supported by the National Cancer Institute (grant numbers K08CA133103 and P01CA109901), the Leukemia and Lymphoma Society, the William Lawrence Blanche Hughes Foundation, the Bear Necessities Foundation, the Ligue Nationale contre le Cancer, Association Laurette Fugain, Institut National du Cancer (INCA), Universités Paris Diderot and Paris Sud, INSERM, CEA and Canceropole Ile de France, European Union's Seventh Framework Programme and the American Society of Hematology.
The Dana-Farber/Boston Children's Cancer and Blood Disorders Center brings together two internationally known research and teaching institutions that have provided comprehensive care for pediatric oncology and hematology patients since 1947. The Harvard Medical School affiliates share a clinical staff that delivers inpatient care at Boston Children's Hospital and outpatient care at the Dana-Farber Cancer Institute's Jimmy Fund Clinic. Dana-Farber/Boston Children's brings the results of its pioneering research and clinical trials to patients' bedsides through five clinical centers: the Blood Disorders Center, the Brain Tumor Center, the Hematologic Malignancies Center, the Solid Tumors Center, and the Stem Cell Transplant Center.
Irene Sege | EurekAlert!
The Great Unknown: Risk-Taking Behavior in Adolescents
19.01.2017 | Max-Planck-Institut für Bildungsforschung
A sudden drop in outdoor temperature increases the risk of respiratory infections
11.01.2017 | University of Gothenburg
An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...
Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales
Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
19.01.2017 | Event News
10.01.2017 | Event News
09.01.2017 | Event News
19.01.2017 | Earth Sciences
19.01.2017 | Life Sciences
19.01.2017 | Physics and Astronomy