Bortezomib-induced polyneuropathy
Background
One of the most frequently used substances for the multiple myeloma treatment is the proteasome inhibitor bortezomib. It inhibits the activity of certain protein complexes in cancer cells and thus tumour growth. One of the known side effects is peripheral neuropathy, which manifests itself as numbness, tingling and even severe pain in the upper and lower extremities. It is unknown why this side effect occurs in some patients and can even become chronic.
Research objective
In project 1 of KFO 5001, the development and resolution patterns of nerve pain in patients treated with bortezomib for multiple myeloma will be analysed in longitudinal and cross-sectional studies. The study will consider the individual genetic predisposition, changes in mRNA and barrier proteins that are located in the cell membrane to protect against nerve damage. Furthermore, we will observe the effects on microtubules and receptors, such as the sensitive TRPV1 pain receptors in cutaneous nerves.
Implementation
Innovative structural and functional MRI methods will be used to visualize the changes in human nerves and dorsal root ganglia in clinically defined patients and thus to reveal the disease-specific causes of pain development. From the same patient cohort, we will analyse the social environment and its influence on the peripheral nervous system. In parallel, corresponding animal models for the resolution of bortezomib-induced polyneuropathy are investigated in rats, the fruit fly Drosophila and mice.
Focus on the PKNOX1 gene
We aim to analyse the role of the gene PKNOX1 in its different manifestations and variants in the development of pain. Previous studies have shown that certain polymorphisms of this gene, which is involved in the regulation of inflammation, are associated with an increased pain reaction to bortezomib. Therefore, the researchers want to generate neurons from the skin cells of affected patients in the laboratory using induced pluripotent stem cells (hiPSCs) to determine which genetic polymorphisms lead to which changes in neurons.
Significance
An improved understanding of the pathomechanisms underlying bortezomib-induced polyneuropathy is necessary for the targeted use of this important drug to treat multiple myeloma. Patients often stop medication, not because of lack of efficacy, but due to its painful side effects. New findings should therefore also help to develop efficient and possibly personalized strategies to alleviate the symptoms for those affected.
Research Team P1
Head
Univ.-Prof. Dr. Martin Kortüm, MD
Chair of Translational Myeloma Research
University Hospital Würzburg
Univ.-Prof. Dr. Hermann Einsele, MD
Head of the Department of Internal Medicine II
University Hospital Würzburg
Univ.-Prof. Dr. Claudia Sommer, MD
Speaker of KFO 5001
Deputy Head of the Department of the Neurology
University Hospital Würzburg
Members of the team
Dr. rer. nat. Umair Munawar, Researcher
Dr. Xiang Zhou, MD, Clinician Scientist
Nadine Cebulla, PhD Student
Leon Flamm, PhD Student
Nicola Giordani, PhD Student
Johanna Güse, PhD Student
Seungbin Han, PhD Student
Laura-Isabel Jähnel, PhD Student
Calvin Terhorst, PhD Student
Annett Wieser, PhD Student
