Acute lymphoblastic leukemia (ALL) is a rare cancer that affects mostly affects children. In the search for new therapeutic options, researchers at Vetmeduni Vienna have now discovered a new mechanism of disease development and proposed a completely new treatment - a pioneering work for future cancer therapies. The study has just been published in Nature Communications.

 

Cyclin-dependent kinases (CDKs) are frequently deregulated in cancer and represent promising drug targets. The research team of Veronika Sexl at the Vetmeduni Vienna - in collaboration with the research team of Nathanael Gray from Harvard Medical School (USA) - focused on CDK8 in the search for new therapeutic routes for ALL. The reason for this is that tumorigenic cells are dependent on CDK8 function, while healthy cells are not. This opens up a therapeutic window by targeting CDK8: healthy cells are spared while cancer cells will be affected.

The research team was able to show that leukemia cells that lose CDK8 in leukemia mouse models significantly enhance disease latency and prevents disease maintenance. Furthermore, CDK8-depleted cancer cells are highly sensitive to mTOR inhibitors, a previously unknown connection. Thus, the authors have synthesized a small molecule (YKL-06-101) that combines mTOR inhibition and degradation of CDK8, and induces cell death in human leukemic cells. This represents a new therapeutic line in drug development: a dual degrader drug is sufficient to break down a molecule - CDK8 - and at the same time enzymatically block a signalling pathway. They propose that by affecting both simultaneously a potential therapeutic strategy for the treatment of ALL patients might be developed.

Published in Nature Communications

Ingeborg Menzl, Tinghu Zhang, Angelika Berger-Becvar, Reinhard Grausenburger, Gerwin Heller, Michaela Prchal-Murphy, Leo Edlinger, Vanessa M. Knab, Iris Z. Uras, Eva Grundschober, Karin Bauer, Mareike Roth, Anna Skucha, Yao Liu, John M. Hatcher, Yanke Liang, Nicholas P. Kwiatkowski, Daniela Fux, Andrea Hoelbl-Kovacic, Stefan Kubicek, Junia V. Melo, Peter Valent , Thomas Weichhart, Florian Grebien, Johannes Zuber, Nathanael S. Gray and Veronika Sexl

Doi: https://doi.org/10.1038/s41467-019-12656-x

Iris Uras Jodl, from the Institute of Pharmacology and Toxicology at Vetmeduni Vienna, was awarded the Wilhelm Türk Prize of the Austrian Society for Hematology & Medical Oncology for the best scientific work in the field of hematology. The award ceremony took place on October 12th 2019 as part of the joint annual conference of the German, Austrian and Swiss societies for hematology and medical oncology, in Berlin.

The Wilhelm Türk Prize is primarily intended to promote young scientists and is awarded once a year for outstanding research work in the field of hematology. The award is endowed with € 5,000. This year Iris Uras was able to convince the reviewers with her article "Cdk6 coordinates Jak2 V617F mutant MPN via NFkB and apoptotic networks" published in journal Blood, under the supervision of Veronika Sexl. Uras Jodl researched the role of Cyclin-dependent kinase 6 (CDK6) in the development of myeloproliferative neoplasia (MPN) using mouse models.

Christoph Binder,
Department of Laboratory Medicine MedUni Vienna,
Center for Molecular Medicine (CeMM), Austrian Academy of Sciences

Title: Oxidation-specific epitopes act as danger-associated molecular pattern in chronic inflammation

https://www.meduniwien.ac.at/hp/phd-mst/research-labs/christoph-j-binder-md-phd/

Christoph Binder is interested in the immune mechanisms of atherosclerosis and the immune recognition of oxidation-specific epitopes, and particularly how these responses can be exploited to protect from atherosclerotic lesion formation.