An international team of scientists from Lenka Bešše's laboratory at the Department of Biology and colleagues from German and Swiss institutions have published joint research results on the effects of proteasome inhibition in multiple myeloma. These results offer new possibilities for using already approved and clinically available drugs.
Multiple myeloma, a malignant disease of plasma cells, is the second most commonly diagnosed haematological tumour after non-Hodgkin's lymphoma. Modern and highly effective drugs used in its treatment include carfilzomib (available under the trade name Kyprolis), a second-generation proteasome inhibitor. It blocks proteasome activity with high efficiency and in a specific manner. Proteasome inhibition is particularly effective in treating multiple myeloma because myeloma cells are highly dependent on the proper functioning of the proteasome, which, under physiological conditions, ensures the recycling of intracellular proteins.
New treatments for patients with multiple myeloma include immunotherapy based on T lymphocytes that carry a chimeric antigen receptor (CAR) directed against the BCMA protein (CAR-BCMA). Research by Professor Florian Bassermann's team at the Technical University of Munich has shown that BCMA is recycled via the proteasome in multiple myeloma cells. This process can cause a reduced presence of BCMA on the cell surface, preventing CAR-BCMA lymphocytes from recognising and destroying tumour cells.
Initial studies show that proteasome inhibition with carfilzomib can halt this recycling process and stabilise BCMA levels on the cell surface. Combining carfilzomib with CAR-BCMA therapy may improve treatment response and enhance the effects of therapy in patients for whom CAR-BCMA treatment alone is not sufficiently effective.
However, the use of carfilzomib also has its risks. At higher doses, it can cause severe cardiovascular toxicity due to strong proteasome inhibition. Research shows that this cardiac toxicity is related to a specific mechanism of action of carfilzomib, which affects two key cellular processes: retinoic acid (vitamin A) metabolism and the renin-angiotensin system. The administration of drugs acting on these pathways—specifically, all-trans retinoic acid (atRA) and valsartan—has been shown to reduce cardiotoxicity in experimental models. Combining carfilzomib with the above-mentioned drugs may therefore be one way to reduce the adverse effects of treatment while maintaining its antitumor efficacy.
The research results offer new possibilities for using already approved and clinically available drugs. In the first case, it is a combination of immunotherapy with a proven therapy for treating multiple myeloma, which increases the effectiveness of immunotherapy even in patients who lose response. In the second case, it involves mitigating the side effects of treatment that prevent the drug from being administered in the required dose, thereby preventing its full antitumor potential from being realised.
The above-mentioned results were achieved through international cooperation. In the first case, Lenka Bešše's research group from the Department of Biology at the Faculty of Medicine of Masaryk University collaborated on a project at the Technical University of Munich (Florian Bassermann's research group), which also involved the University Hospital in Würzburg and the Cantonal Hospital in St. Gallen, Switzerland. The second publication is the result of joint work by scientists from the Faculty of Medicine of Masaryk University and the Cantonal Hospital in St. Gallen, with the support of the Institute of Biomedical Research in Bern and the University Hospital in Würzburg.
The new findings were published in the online journals Blood and iScience.
Lenka Bešše's research group is part of the National Cancer Research Institute, which was established thanks to support from the National Recovery Plan project.
A breakthrough scientific discovery is only the beginning. An equally demanding journey leads from the laboratory toward real-world application—toward technologies that can help patients, advance medicine, or boost agricultural yields. Participants in the first run of the Life Science Transfer Academy, a two-month educational program for young life science researchers, set out to understand how to navigate this path.
This webinar will be held on Tuesday, December 9th, at 8AM CEST, and will be led by Dr. Lym Frumkin.
