Project Details
Projekt
Bortezomib-induced painful neuropathy: risk factors, resilience and resolution
Applicants
Professor Dr. Hermann Einsele; Professor Dr. Martin Kortüm; Professorin Dr. Claudia Sommer
Subject Area
Molecular and Cellular Neurology and Neuropathology
Hematology, Oncology
Clinical Neurology; Neurosurgery and Neuroradiology
Hematology, Oncology
Clinical Neurology; Neurosurgery and Neuroradiology
Term
since 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 426503586
Bortezomib (BTZ) is the mainstay of multiple myeloma (MM) treatment. Painful neuropathy is the dose limiting complication in at least 30% of treated patients and an important cause of underdosing. Neuropathy is mild in some patients with prompt resolution after ending BTZ therapy, but can be deleterious in others. We will use a patient-centered combined genetic and morphological/biochemical approach to uncover denominators of resolution or non-resolution of BTZ-induced peripheral neuropathy (BIPN). Specifically, we aim to translate findings from the preclinical models back to patients. A candidate genetic locus for BTZ neurotoxicity maps to the proinflammatory regulator PKNOX1. PKNOX1 is a target of the microRNA-223, which favors proinflammatory macrophage activation. In animal models BTZ induces proinflammatory changes with increased production of proinflammatory cytokines and reduced levels of brain derived neurotrophic factor (BDNF). BTZ further affects polymerization of alpha-tubulin and results in microtubule stabilization. An increased expression of the transient receptor potential channel vanilloid 1 (TRPV1) and the transient receptor potential ankyrin 1 (TRPA1) has been implied as a cause for pain behavior in a BIPN rat model. We will investigate whether these mechanisms apply to BIPN in humans, and if they are related to resolution. To this end, we will analyze DNA from patients with MM (n=120) that are either planned for BTZ treatment (Group 1), are presently under BTZ treatment (Group 2), or are long term survivors with past BTZ treatment (Group 3). Groups 1 and 2 will be followed up at two 3-monthly intervals for development and/or resolving of neuropathy. Further follow-up will be at 6-monthly intervals. Group 3 will serve as a cross-sectional cohort of patients who either never had BIPN, in whom it has resolved, or who still suffer from it. We will screen our patients for a SNP in the PKNOX1 gene (rs2839629) and for the BDNF Val66Met polymorphism (rs6265) that has also been associated with pain. In addition, we will screen for epimutations that may lead to an altered promotor activity of both genes. Levels of microRNA-223 in patients’ white blood cells will be determined to test the hypothesis of an influence of this microRNA on BTZ-induced inflammation and pain. Patients’ blood samples will be analyzed to examine whether the findings from BTZ animal models (cytokines, BDNF, neurofilament light chain) are translatable to the human disease. We will analyze skin innervation, including TRPV1 and TRPA1 expression, macrophage subtypes, natural killer cells and axonal pathology with light and electron microscopy as well as the transcriptome in patients’ skin punch biopsies. This combined approach will allow translation from already available preclinical data to the clinic and will help to better understand BIPN and to identify new targets for its prevention and resolution.
DFG Programme
Clinical Research Units
