The team headed by Daniel Krappmann has discovered a new, unexpected effect of drugs that have been in use since the 1950s to treat psychotic disorders. In malignant lymphoma these anti-psychotics inhibit the MALT1 enzyme and thus cause cancer cells to die. This new approach to the treatment of an aggressive form of lymphoma is published in the December edition of the renowned scientific journal Cancer Cell.
Mepazine* and Thioridazine*, two anti-psychotics that have been in use since the 1950s, inhibit the MALT1 protease and thus develop a new, specific anti-tumor effect in a highly malignant sub-group of diffuse large B-cell lymphoma*. This surprising discovery has now been published in Cancer Cell by the team of scientists led by Dr. Daniel Krappmann, Head of the Department of Cellular Signal Integration at the Institute of Molecular Toxicology and Pharmacology. As diffuse large B-cell lymphoma is one of the most common malignant lymphoma, there is an urgent clinical need to develop effective medication.
Daniel Nagel from the Helmholtz Zentrum München and first author of the study tested the ability of about 18,000 substances to inhibit the MALT1 protease. The screen was conducted using the ChemBioNet collection at the Screening Unit of the Leibniz Institute of Molecular Pharmacology (FMP). Among the compounds identified, the well-known anti-psychotics Mepazine and Thioridazine were among the best MALT1 inhibitors. Preclinical data demonstrate that inhibiting the MALT1 protease causes the killing of the tumor cells. The results open up possibilities for clinical trials involving the use of Mepazine and Thioridazine in the targeted treatment of lymphoma patients. The preclinical studies were conducted in close cooperation with the Institute of Molecular Immunology at the Helmholtz Zentrum München, the Charité – Universitätsmedizin Berlin and the Philipps-Universität Marburg.
“It is an enormous advantage that both substances have been in clinical use for so long,” said Dr. Daniel Krappmann, who headed the study. “Many side-effects have therefore been well examined, and that enables us to initiate clinical studies faster. We still have a long way to go, but if the positive effect is also confirmed in patients, our work could, in fact, point the way towards a new, personalized concept for the treatment of malignant lymphoma.” As different mechanisms are responsible for the anti-psychotic effects and the anti-tumor action of the identified molecules, further work will now focus on developing new active compounds. Specific MALT1 inhibitors without anti-psychotic side effects could greatly increase the chances for a new effective treatment of lymphoma patients.
* Mepazine and Thioridazine were first used in the 1950s as anti-psychotic drugs. Mellaril/Thioridazine is still approved today for the treatment of chronic psychotic patients.
* Diffuse large B-cell lymphoma (DLBCL) is the most frequently occurring group of non-Hodgkin lymphoma (NHL). Each year, between 3 and 5 out of every 100,000 people develop this form of cancer. The MALT1 protease contributes to the pathology of the ABC lymphoma, which account for about one third of all DLBCL. With a 5-year survival rate of below 50% the ABC lymphoma constitutes the most aggressive sub-type of all DLBCL. ABC stands for “activated B cell-type”.
Nagel D. (2012), Pharmacologic Inhibition of MALT1 Protease by Phenothiazines as a Therapeutic Approach for the Treatment of Aggressive ABC-DLBCL. Cancer Cell, Volume 22, Issue 6, 11 December 2012, Pages 825–837.
The Helmholtz Zentrum München, the German Research Center for Environmental Health, pursues the goal of developing personalized medical approaches to the prevention and therapy of major common diseases such as diabetes and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München has about 2,000 staff members and is headquartered in Neuherberg in the north of Munich. It is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 34,000 staff members. The Helmholtz Zentrum München is a partner in the German Center for Diabetes Research. www.helmholtz-muenchen.de
Dr. Daniel Krappmann, Helmholtz Zentrum München – German Research Center for Environmental Health (GmbH), Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Ingolstädter Landstr. 1, 85764 Neuherberg – Tel.: +49 89-3187-3461. E-Mail