MiR-155 and RUNX function in neurofibroma tumorigenesis and therapy

首席调查员/项目主任(最后、第一、中间)：吴建强 使用技术语言的项目摘要，简要描述实现所述目标的研究设计和基本原理 1型神经纤维瘤病(NF1)是一种遗传性疾病，易患上 良性雪旺细胞瘤称为丛状神经纤维瘤(PNFS)。目前，对PNFS的预防是 这是不可能的，部分原因是肿瘤发生的分子机制还没有完全了解。 手术治疗仍然是PNFS的主要治疗方法。FDA批准了细胞抑制MEK抑制剂， Selumetinib(Koselugo)，可使70%的人肿瘤缩小，但停药后肿瘤重新生长 治疗。因此，治疗神经纤维瘤的新策略和新靶点是 急需之物。内质网(ER)应激反应通路在 在几种癌症中的肿瘤生长和治疗，但在神经纤维瘤方面仍未被研究。瞄准这些人 内质网应激通路可能为PNF患者提供一种新的治疗方法。 我们新的初步数据显示：a)所有三个内质网应激信号通路在 老鼠和人类的PNF都与对照组进行了比较。B)击倒蛋白激酶类RNA ShRNA介导的内质网激酶(PERK)减少细胞内神经纤维瘤样瘤的数量 裸鼠移植模型的建立。C)含Valosin蛋白(VCP)的药理抑制 与MEK抑制剂(Meki)一起抑制细胞增殖，增加细胞凋亡，并 诱导蛋白质泛素化。我们的中心假设是SC/SCP中NF1的丢失导致PNF 通过驱动RUNX和VCP调节的蛋白平衡来适应内质网应激信号的形成，从而 靶向蛋白平衡为PNF患者提供了细胞毒治疗。提出了两个具体目标： 在目标1中，我们将确定RUNX和VCP是否以及如何调节蛋白质的合成和降解 维持蛋白质平衡，使NF1-/-SC/SCPs适应内质网应激，从而推动PNF的启动和 成长。在目标2中，我们将测试是否通过针对VCP(单独或 与Meki相结合)提供细胞毒性，从而持久地控制PNF的生长，并确定 作用机制。 总体而言，该提案将提供RUNX1/3和可能的VCP的机械证据- 依赖蛋白平衡和适应性内质网应激信号在PNF形成中的癌基因作用 并为MEK非依赖性临床试验提供临床前理论依据。

Principal Investigator/Program Director (Last, first, middle): Wu, Jianqiang Project summary Using technical language, briefly describe the research design and rationale for achieving the stated goals Neurofibromatosis type 1 (NF1) is an inherited disease predisposing affected individuals to benign Schwann cell tumors called plexiform neurofibromas (PNFs). Currently, prevention of PNFs is not possible, partly because the molecular mechanisms of tumorigenesis are not fully understood. Surgery remains the mainstay of therapy for PNFs. The FDA approved cytostatic MEK inhibitor, Selumetinib (Koselugo), shrinks tumor in 70% of individuals but tumors regrow after stopping drug treatment. Therefore, new therapeutic strategies and targets for the treatment of neurofibroma are urgently needed. The endoplasmic reticulum (ER) stress response pathways play pivotal roles in tumor growth and therapy in several cancers but remain unstudied in neurofibroma. Targeting these ER stress pathways might provide a novel therapy for PNF patients. Our new preliminary data show that: a) All three ER stress signaling pathways are activated in both mouse and human PNFs compared to controls. b) Knock down of protein kinase RNA-like endoplasmic reticulum kinase (PERK) by shRNA decreases neurofibroma like tumor number in a cell transplantation model in nude mice. c) Pharmacological inhibition of valosin-containing protein (VCP) together with a MEK inhibitor (MEKi) decreases cell proliferation, increases cell apoptosis and induces protein ubiquitination. Our central hypothesis is that loss of Nf1 in SC/SCPs leads to PNF formation by driving Runx- and VCP-regulated proteostasis to adapt to ER stress signaling, so that targeting proteostasis provides cytotoxic therapy for PNF patients. Two specific aims are proposed: In aim 1, we will determine if and how Runx and VCP regulate protein synthesis and degradation to maintain proteostasis so that Nf1-/- SC/SCPs adapt to ER stress, thereby driving PNF initiation and growth. In aim 2, we will test whether overwhelming irresolvable ER stress by targeting VCP (alone or in combination with MEKi) provides cytotoxic and, thus, durable control of PNF growth, and determine the mechanism of action. Overall, this proposal will provide mechanistic evidence of Runx1/3 and possible VCP- dependent proteostasis and adaptive ER stress signaling functions as oncogene on PNF formation and provide pre-clinical rationale for MEK-independent clinical trials.