Chronic myeloid leukemia (CML) is caused by a degeneration of the hematopoietic stem cells (leukemia cells), thus leading to the uncontrolled formation of specific white blood cells, the so-called granulocytes.
Research work at the Department of Medical Oncology at Inselspital, Bern University Hospital and the University of Bern therefore focused on identifying signaling pathways and leukemia cell gas control mechanisms. A promising method is provided by working with MPR, an anti-emetic drug commonly used to treat nausea and vomiting.
Specific inhibition of leukemia gas proliferation with metoclopramide
The exact role of surface CD93 molecules (accumulation of difference 93) in controlling the proliferation of leukemia cells was investigated, first in animal experiments and later in the tests with leukemia stem cells from patients. This revealed a specific regulatory action of CD93 in leukemia gas cells.
Initially, the effect was demonstrated in vivo in animal experiments. It has also been shown that the control action applies only to leukemia stem cells, not to normal hematopoietic stem cells.
In addition, the anti-emetic MPR has been shown to disrupt the signaling pathway that stimulates cell proliferation of leukemia cells in vitro and also, in animal experiments, visibly improves survival with CML by inhibiting the proliferation of leukemia cells. This provides strong evidence that MPR may also show positive results in the treatment of CML in humans.
Extensive research
The study presented in this publication involved a very extensive study.
This is also true of the participating interdisciplinary teams from the Department of Medical Oncology, the Department of Biomedical Research, the Institute of Cell Biology and the Department of Orthopedic Surgery and Hematology at the University Hospital of Bern and the University of Bern. Prof. Dr. nat. Carsten Riether explains:
To develop a new, promising approach to countering CML, contributions from a number of disciplines were required and different audit approaches had to be followed. In a screening method, we obtained the candidate Metoclopramide and subsequently were able to demonstrate its effect on the CD93 signaling pathway in in-vitro and in-vivo trials. “
The research infrastructure in Bern is heavily designed for such large projects. The experience in basic research of the Department of Biomedical Research (DBMR) and in clinical research at the University Hospital is closely linked and can produce strong results.
What are the next research activities?
The results have identified CD93 as a specific regulator responsible for leukemia gas cell proliferation. This marks a promising pathway to target leukemia stem cells. Further studies now need to determine the clinical impact and relevance. Dr. Adrian Ochsenbein describes the following photograph:
“Thanks to this field of knowledge, we were able to identify Metoclopramide as a promising candidate for CML therapy. And with our extensive research infrastructure and our excellent national and international network, we hope it will able to present clinical results within its reasonable timescale.
Source:
Inselspital, Bern University Hospital
Magazine Reference:
Riether, C., et al. (2021) CD93-mediated autoimmune metoclopramide treatment blocks of malignant myeloid leukemia cells. Cell reports. doi.