Project Details
Projekt
Dissecting the spatio-temporal dynamics of bone marrow fibrosis in MPN in response to therapy
Subject Area
Hematology, Oncology
Term
since 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 417911533
In the first funding period of the CRU, we sought to dissect the cellular and molecular step-wise transformation process of the effector cells of bone marrow fibrosis in response to a malignant hematopoietic clone. Ultimately, we aimed to reveal novel markers for diagnostics of early disease stages and identify urgently needed anti-fibrotic therapeutics to stop the disease progression. We have reached this ambitious goal: we 1) revealed the step-wise transformation of fibrosis-driving cells on the single cell level, and 2) identified disease-specific mechanisms in these fibrosis-driving cells as the long-sought biomarker and therapeutic target in bone marrow fibrosis related to blood cancer. Specifically, we identified the alarmin heterodimer S100A8/S100A9- not only as an early diagnostic but also an actionable biomarker. Importantly, we showed that targeting these alarmins with the small molecular oral inhibitor Tasquinimod stopped the progression of fibrosis. Based on these findings we have initiated a clinical proof-of-concept trial “TasquForce MPN” (recruitment in late summer 2022). Despite an improved understanding of fibrosis-driving cells, clinical trials in MPN so far have only demonstrated a modest effect at best and have not been able to reverse established fibrosis. Currently, the only potentially curative option is allogeneic stem cell transplant (allo-HSCT) - a prime example for fibrosis resolution. In the second funding period, we will apply cutting edge spatial and single cell multi-omics technologies in a concerted and integrated manner, in a serially collected and clinically well-annotated cohort of MPN patients who are undergoing allo-HSCT. Through this, we will be able to precisely understand mechanisms in the regression and resolution of bone marrow fibrosis to achieve two aims: 1) to find biomarkers predicting the outcome of allo-HSCT on fibrosis and graft-function and 2) to improve graft function and resolution of fibrosis, and hence improve survival. We will utilize state of the art and unique novel in vitro models (patient-derived induced pluripotent stem cells (iPSCs); organotypic cultures) to validate key mechanisms and therapeutic targets with subsequent lead discovery.
DFG Programme
Clinical Research Units
