Innovation and Translation

Antipsychotic Drugs Tested against Malignant Lymphomas

For Daniel Krappmann, in retrospect everything seems so clear and obvious. In view of their groundbreaking findings, the excitement was palpable among Krappmann and his 15-member team until the study was published: The researchers discovered that ­specific drugs used since the 1950s to treat psychotic disorders can also be used as ­cancer ­treatment against malignant lymphomas. The substances inhibit the enzyme MALT1 ­leading to the death of cancer cells. This could mean a breakthrough in cancer research.

Daniel Krappmann is studying the MALT 1 protease enzyme as new approach for the treatment of malignant lymphomas. With support from the Helmholtz Validation Grant and the Department of Innovation Management, the team of the research unit Cellular Signal Integration led by Krappmann found potential enzyme inhibitors, which then were licensed for therapeutic further development. Image: signaling protein visualized with an immunofluorescence microscope. Source: Quelle: HMGU

Many years of intensive preparatory work, coupled with determination and the necessary bit of luck led to this success. Since 2008, Daniel Krappmann, head of the research unit Cellular Signal Integration at the Institute of Molecular Toxicology and Pharmacology at Helmholtz Zentrum München, has been investigating the MALT1 protease, which he had recognized as a particularly interesting enzyme. “It is the only enzyme in this class in humans, and is thus very exclusive,” the 45-year-old biologist said. He not only analyzed its enzymatic effectiveness, but using genetic methods, also explored the effects of the MALT1 protease on the immune system. In addition, his team, together with scientists from Technische Universität München, was able to show that aggressive lymphoma cells are not viable without the activity of MALT1.

After all this was known, Krappmann decided to look for compounds that can inhibit MALT1, since such substances would provide good starting points for drugs for the treatment of lymphomas or autoimmune diseases. His doctoral candidate Daniel Nagel took on the task and tested 18 000 substances in cooperation with the Leibniz-Institut für Molekulare Pharmakologie in Berlin. After many test runs and further analyses in cooperation with Charité Universitätsmedizin Berlin, it became apparent that the long-known antipsychotic drugs mepazine and thioridazine were among the best MALT1 inhibitors.

"It is a huge advantage that both drugs have long been in clinical use," said Krappmann. "Many side effects have been extensively studied, and this allows us to quickly initiate clinical trials." These will now begin parallel to further trials that will be carried out on
the effect of the substances in autoimmune diseases.

According to Krappmann, Helmholtz Zentrum München offers excellent conditions for such research. Here researchers find expertise in a variety of disciplines, from biochemistry and immune research to preclinical testing. Meanwhile, a separate screening unit has been established for drug discovery at the Center.

Added to this was the financial support from the Helmholtz Validation Grant, the new funding instrument of the Helmholtz Association. The funding for the project amounted to around 950 000 euros, half of which came from the Helmholtz Association and the other half from Helmholtz Zentrum München. The financial support from this fund shall enable scientists from Helmholtz centers to develop their project ideas into commercial results within two years. That is exactly what happened in Krappmann’s project.

The successful identification of a MALT1 inhibitor will also raise the awareness of the pharmaceutical industry for developments and projects within the Helmholtz Association and, over the medium term, significantly promote strategic partnerships. Thus, innovative solutions for patients and even personalized medicine approaches will become possible: “In the future, special biomarkers may enable the identification of patients who respond to treatment with a MALT 1 inhibitor,” said Daniel Krappmann. “Our long-term goal is quite clear – to replace standard treatment with personalized treatment, i.e. with a treatment protocol designed for the individual patient.”

All in all, a great success for Innovation Management at Helmholtz Zentrum München. Here in an exemplary way, basic research findings are translated into applications – thus increasing the value creation of the Center immensely. “It is only possible to pursue such research approaches consistently in an interdisciplinary research environment,” Krapp­mann said. “With our study we have shown that it really can be done!“