Targeting complement 5a-mediated immunoregulation for neurofibroma therapy

主要研究者/项目负责人（末位、首位、中位）：吴建强/Ratner，Nancy 摘要 1型神经纤维瘤病（NF 1）是一种常见的遗传性人类疾病，发病率约为1：2500 世界各地的个人。大约一半的NF 1患者发展为丛状神经纤维瘤，良性，但 破坏性的周围神经肿瘤;由于整合，手术切除通常是不可能的。 关键周围神经肿瘤。我们发现，MEK抑制缩小了70%的肿瘤， DhhCre; Nf 1fl/fl神经纤维瘤荷瘤小鼠。在小鼠模型中的这一结果预测了 针对NF 1和大型不可手术的丛状神经纤维瘤儿童的I/II期临床试验，其中 使用Selumetinib的MEK抑制显示出前所未有的活性，70%的患者 出现持续的部分反应然而，最大肿瘤体积减小50%， 持续的反应需要持续的MEK抑制。因此，我们寻找 基因、蛋白质和途径不能通过MEK抑制正常化。基于我们承诺 初步数据，我们将测试靶向其中之一，C5 a/C5 aR的治疗效果 丛状神经纤维瘤的通路。本申请中提出的工作将测试C5 a是否为 用于丛状神经纤维瘤的治疗靶点，单独或与MEK抑制组合。我们将 测量PK和PD以及功效。我们的多学科团队包括神经纤维瘤领域的世界领导者 临床前测试，神经纤维瘤体积测量专家，生物统计学家，以及 开发独特的C5 aR拮抗剂的补体系统生物学专家，以及 NF 1临床医生。

Principal Investigator/Program Director (Last, first, middle): Wu, Jianqiang/Ratner, Nancy Abstract Neurofibromatosis type 1 (NF1) is a common inherited human disorder affecting about 1:2500 individuals worldwide. About half of NF1 patients develop plexiform neurofibromas, benign but devastating peripheral nerve tumors; surgical removal is often impossible due to the integration of tumor in critical peripheral nerves. We found that MEK inhibition shrinks 70% of tumors in DhhCre;Nf1fl/fl neurofibroma-bearing mice. This result in a mouse model predicted success of a phase I/II clinical trial for children with NF1 and large inoperable plexiform neurofibroma, in which MEK inhibition using Selumetinib in showed unprecedented activity, with 70% of patients experiencing sustained partial responses. However, the maximal tumor volume decrease was 50%, and continued MEK inhibition was required for sustained response. Therefore, we searched for genes, proteins, and pathways that are not normalized by MEK inhibition. Based on our promising preliminary data, we will test the therapeutic effects of targeting the one of these, the C5a/C5aR pathway in plexiform neurofibroma. The work proposed in this application will test if C5a is a therapeutic target for plexiform neurofibromas, alone or in combination with MEK inhibition. We will measure PK and PD, and efficacy. Our multidisciplinary team includes world leaders in neurofibroma preclinical testing, an expert in volumetric measurement for neurofibroma, a biostatistician, and experts in the biology of the complement system who developed unique antagonists of C5aR, and NF1 clinicians.