Coordination Funds

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，我们成功地1)在单细胞水平上解剖了MPN的间质细胞室，2)揭示了疾病进展所特有的炎性细胞因子的分泌，3)了解了衰老在疾病过程中的作用，4)发展了新的疾病模型。这些调查结果现在使我们能够加强对第二个资助期目标的翻译重点。Ib/II期TasquForce MPN临床试验将评估针对ALARIN异源二聚体S100A8/A9的小分子抑制剂tasquiimod对MF患者的疗效和耐受性，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这一成功模式用作第二个资助期的模板--直接将我们的发现应用于患者。在这里，我们将利用服务项目(SP)安装的数据仓库作为中心资源来验证我们在主要人类材料的临床前模型中的发现，并伴随着临床数据注释。通过本提案中概述的工作，我们将更好地了解MPN克隆(P5、P6、SP)早期扩张的关键驱动因素和障碍，以及其中哪些适合于进展为明显的骨髓纤维化的预防策略，例如早期应用干扰素或去甲基化药物，以及纳米药物和受体融合蛋白对抗促炎细胞因子(P2、P4、P5、P6、SP)。此外，我们将生成和评估骨髓纤维化的时空和表观遗传学信息，以确定新的治疗靶点，优化和预测异基因干细胞移植(P1、P2、P3、P4、SP)的成功。总之，这些项目将使我们能够为早期MPN患者设计更好的早期诊断和预防MPN进展的方法，并为晚期MPN患者，特别是显性MF患者设计更好的治疗方案。

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.