Project Details
Projekt
Targeting the bone marrow inflammatory niche in myelofibrosis with nanomedicine therapeutics
Subject Area
Hematology, Oncology
Term
since 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 417911533
The fibrotic bone marrow (BM) in classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) is composed of hematopoietic cells and non-hematopoietic stroma cells, both fueling proliferation, survival and transformation of each other. The malignant clone carries mutually exclusive driving oncogenes: JAK2V617F, mutated calreticulin or thrombopoietin receptor. The reciprocal manipulation of the malignant clone and its progenies, e.g., dysplastic megakaryocytes, and the stroma generates an inflammatory milieu and cause the reprogramming into a disease driving BM microenvironment including fibrotic tissue formation (myelofibrosis). The aberrant reprogramming of the niche disturbs on one hand the expression of diverse inflammatory factors and on the other, the rhythmic regulation of cell cycle and proliferation. The circadian clock and implicated genes are responsible for the tuning of many physiological functions, such as metabolism, angiogenesis, and inflammation. The dysregulation of circadian clock genes has been associated to cancer formation including acute myeloid leukemia. We observed the dysregulation of circadian clock gene expression in CD34+ MPN cells and mutated megakaryocytes and the upregulation of the fibrosis driving factor sulfatase 2 (SULF2), which can be targeted by the hormone melatonin. In addition, we established directed nanoformulations for enhancing the transportation of therapeutics into specific organs, such as the spleen and the BM. Here, we will now (i) evaluate the dysregulated circadian clock as potential therapeutic target in MPN, (ii) investigate the role of SULF2 in myelofibrosis, and (iii) analyze the efficacy of the combination of approved and novel drugs in MPN. For all three objectives, we will develop nanomedicine formulations for delivering small molecule inhibitors, as well as siRNA-based therapeutics in vivo and combine the data with ex vivo complementary techniques, such as single-cell RNAseq and multiplex staining. The ability to perform dual-therapeutic loading in a single formulation and decorate these formulations with active targeting ligands will facilitate the delivery of combination therapies to individual cell-targets. In addition, we will utilize multiscale and multimodal imaging for monitoring non-invasively the disease progression and biodistribution of the various nanotherapeutics in vivo. In summary, by applying image-guided drug delivery strategies we expect to identify the circadian clock as well as SULF2 as druggable targets in MPN and hereby intervene against the myelofibrotic progression.
DFG Programme
Clinical Research Units
