Project Details
Projekt
Resolution of neuropathies caused by bortezomib and its successor drugs
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
Whereas most treatments in multiple myeloma are stopped due to their inefficiency over time and the development of drug resistance, the use of the proteasome inhibitor bortezomib (BTZ) is mainly limited by its neurotoxic effects and the induction of BTZ induced neuropathy (BIPN). In the first funding period, we determined the prevalence of BIPN in a cohort of 112 patients who were prospectively evaluated. We identified neurofilament light chain (NfL) levels in serum as an indicator of acute axonal damage in early BIPN, and we identified increases in CCL-2 and TNF-alpha levels over time as characteristic of non-resolving BIPN. The occurrence of homozygous mutations for both rs2839629 and rs915854 was higher in individuals with painful BIPN, and the homozygous mutated rs2839629 genotype was more prevalent in patients reporting pain compared to those without pain. Thus, either SNP, rs2839629 or rs915854, may indicate an elevated risk of developing painful BIPN. To make use of these findings for preventing BIPN, we now aim to develop a “risk tool” to predict BIPN at an early time point. This tool will integrate clinical and genetic data and biomarkers established in the first funding period, such as serum neurofilament light and proinflammatory cytokines. In parallel, the development of painful neuropathy and its resolution will be examined in patients treated with carfilzomib, a BTZ successor drug (WP1). Patient adherence to treatment and pharmacokinetic profiles will be done to assess the influence of these factors on BIPN resolution (WP4). Blood samples will be used to identify the specific immune cells producing resolution inhibiting or promoting factors. Characterization of distal axonal changes will be performed in skin biopsies using methods established in Z, including spatial transcriptomics to analyse cellular transcriptome changes, and, regarding the axonal proteome, with NP8 (WP2). Patient derived SNPs that were found relevant for BIPN prognosis and genes identified in the drosophila model (P6) to influence resolution will be introduced into cell line models. These models will be treated with BTZ and other proteasome inhibitors to study their influence on the transcriptome and on DNA methylation and results will be integrated into the tool for BIPN risk assessment.
DFG Programme
Clinical Research Units
