Coordination Funds

协调基金

• 批准号: 428857858
• 负责人: Professor Dr. Steffen Koschmieder
• 金额: --
• 依托单位: Klinik für Onkologie, Hämatologie und Stammzelltransplantation (Med. Klinik IV)
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/428857858?language=en
• 关键词: Coordination; Funds

The overall aim of the Clinical Research Unit 344 is to better understand the biology of Myeloproliferative Neoplasms (MPN), with a special focus on myelofibrosis (MF), and to identify new treatment options for patients with MPN-associated MF. In the first funding period, we succeeded to 1) dissect the stromal cell compartment in MPN at the single cell level, 2) reveal inflammatory cytokine secretion specific to disease progression, 3) understand the role of aging in the disease course, and 4) develop novel disease models. These findings now allow an intensified translational focus of our aims for the second funding period. The phase Ib/II TasquForce MPN clinical trial, which will assess the efficacy and tolerability of the small molecule inhibitor tasquinimod, targeting the alarmin heterodimer S100A8/A9, in patients with MF, will start recruiting in late summer of 2022. Our goal is to use this success model from our first funding period as a template for the second funding period – to directly move our findings to application in patients. We will leverage here the data warehouse installed by the service project (SP) as a central resource to validate our findings from pre-clinical models in primary human material accompanied by clinical data annotation. Through the work outlined in the present proposal, we will better understand key drivers of and roadblocks to early expansion of the MPN clone (P5, P6, SP) and which of these are amenable to preventive strategies of progression towards overt myelofibrosis, such as early administration of interferon or demethylating agents, and nanomedicines and receptor fusion proteins against pro-inflammatory cytokines (P2, P4, P5, P6, SP). Moreover, we will generate and evaluate spatio-temporal and epigenetic information of BM fibrosis to identify novel therapeutic targets and optimize and prognosticate the success of allogeneic stem cell transplantation (P1, P2, P3, P4, SP). Together, these projects will allow us to design better means of early diagnosis and prevention of MPN progression in patients with early-stage MPN and better treatment options for patients with later-stage MPN, particularly overt MF.

临床研究单位344的总体目标是更好地了解骨髓增生性肿瘤（MPN）的生物学，特别关注骨髓纤维化（MF），并为MPN相关MF患者确定新的治疗方案。在第一个资助期内，我们成功地1）在单细胞水平上解剖了MPN中的基质细胞区室，2）揭示了疾病进展特异性的炎性细胞因子分泌，3）了解了衰老在疾病过程中的作用，以及4）开发了新型疾病模型。这些发现现在允许我们在第二个资助期内加强目标的转化重点。TasquForce MPN Ib/II期临床试验将评估小分子抑制剂tasquinimod（靶向alarmin异源二聚体S100 A8/A9）在MF患者中的疗效和耐受性，将于2022年夏末开始招募。我们的目标是将我们第一个资助期的成功模式作为第二个资助期的模板-直接将我们的发现应用于患者。我们将在这里利用服务项目（SP）安装的数据仓库作为中心资源，以验证我们在主要人体材料中的临床前模型中的发现，并伴有临床数据注释。透过本建议书所概述的工作，我们会更深入了解早日扩展MPN的主要推动因素和障碍（P5，P6，SP），并且这些中的哪些适合于向明显的骨髓纤维化进展的预防策略，例如早期施用干扰素或去甲基化剂，以及针对促炎性细胞因子的纳米药物和受体融合蛋白（P2、P4、P5、P6、SP）。此外，我们将生成和评估BM纤维化的时空和表观遗传信息，以确定新的治疗靶点，并优化和验证异基因干细胞移植（P1，P2，P3，P4，SP）的成功。总之，这些项目将使我们能够设计更好的早期诊断和预防早期MPN患者的MPN进展的方法，并为晚期MPN患者提供更好的治疗选择，特别是明显的MF。