Thalidomide gained sad notoriety as an active substance in a sleeping pill (marketed in Germany as Contergan): more than 50 years ago, countless babies were born with malformed limbs because their mothers had taken the medication during pregnancy. And yet there is another side to this agent: at the end of the 1990s, thalidomide started being used to alleviate difficult-to-treat bone marrow cancers such as multiple myeloma and myelodysplastic syndrome (MDS) with the loss of chromosome 5q. Dr Jan Krönke was able to investigate just how the immunomodulatory pharmaceutical substances thalidomide and its successor lenalidomide function during a three-year residence at Brigham and Women’s Hospital/Harvard Medical School and at Ulm University Hospital’s Department of Internal Medicine III. Scientists led by Krönke and Prof Benjamin L. Ebert have published their latest findings on the mode of action in MDS in the prestigious journal “Nature“.
Signs of anaemia, bleeding from the gums or gastro-intestinal bleeding, and frequent infections: these symptoms may be an indication of myelodysplastic syndrome which, in the worst case, can develop into acute leukaemia. The drug lenalidomide improves the condition of many patients. And yet the mode of action of lenalidomide and its analogues (thalidomide, pomalidomide) were completely unknown until around one year ago: in 2014, Jan Krönke and his fellow researchers were able to prove that the agent binds to the so-called cereblon ubiquitin ligase – which involves cellular “protein waste disposal”. In this way, some proteins can be specifically degraded. Such proteins include Ikaros and Aiolos, upon which cancer cells in multiple myeloma, for example, are dependent.
But how does the drug work in the case of myelodysplastic syndrome, where only one copy of the chromosome 5q exists? The researchers started searching for additional substrates of the cereblon ubiquitin ligase, which are regulated by lenalidomide, using protein analysis, molecular biological studies and the mouse model.
The result: the drug causes the protein casein kinase 1A (CK1A) to be specifically labelled and degraded via the cereblon ubiquitin ligase. Since the CK1A gene lies on the lost chromosome 5q, MDS cells have small quantities of this protein in any case, and are therefore particularly sensitive to lenalidomide. “Consequently, lenalidomide specifically exploits the loss of a gene in the cancer cells in order to kill them,” explains Krönke, leader of the Emmy Noether Junior Research Group.
Investigations in the mouse model possible for the first time
The group was also able to prove that lenalidomide alone – and not the analogues – has the desired effect in the bone marrow disease. This is significant for the development of new similarly-acting drugs that specifically degrade disease-relevant proteins. After all, it appears that the tiniest chemical modifications change the effect of the starting drug thalidomide.In their investigations, the German-American group of researchers conducted experiments in mouse cells involving lenalidomide for the first time. This had previously been impossible because mice are naturally resistant to the effects of thalidomide/lenalidomide. This is why tests with rodents conducted in the 1950s gave no indication of the disastrous side effects of thalidomide. By genetically modifying the target protein cereblon, the scientists were then able to sensitise mouse cells to lenalidomide, meaning that further investigations can be undertaken in the mouse model in the future.
All in all, the authors, including Ulm’s Heisenberg professor Lars Bullinger (also at Ulm University Hospital’s Department of Internal Medicine III), were able to demonstrate for the first time the mechanism of action of the thalidomide analogue lenalidomide in the bone marrow disease MDS. They also identified a method that enables these substances to be investigated in mouse cells for the first time. Their work was funded by the Deutsche Forschungsgemeinschaft (German Research Foundation, DFG) via Jan Krönke’s Emmy Noether Programme and the Collaborative Research Centre 1074 “Experimental models and clinical translation in leukemia ”. Additional support was provided by the Else Kröner Fresenius College Ulm, and the researchers cooperated with the company Celgene, which produces thalidomide and lenalidomide.
Jan Krönke, Emma C. Fink, Paul W. Hollenbach, Kyle J. MacBeth, Slater N. Hurst, Namrata D. Udeshi, Philip P. Chamberlain, D. R. Mani, Hon Wah Man, Anita K. Gandhi, Tanya Svinkina, Rebekka K. Schneider, Marie McConkey, Marcus Jära, Elizabeth Griffiths, Meir Wetzler, Lars Bullinger, Brian E. Cathers, Steven A. Carr, Rajesh Chopra & Benjamin L. Ebert. Lenalidomide induces ubiquitination and degradation of CK1a in del(5q) MDS. Nature. doi:10.1038/nature14610
Text und Medienkontakt: Annika Bingmann