MiR-155 and RUNX function in neurofibroma tumorigenesis and therapy

MiR-155 和 RUNX 在神经纤维瘤发生和治疗中的作用

• 批准号: 10437402
• 负责人: Jianqiang Wu
• 金额: $ 42.4万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10437402
• 关键词: ATF6 gene; ATP phosphohydrolase; Affect; Apoptosis; Automobile Driving; Benign; Biochemical Genetics; Cell Proliferation; Cell Survival; Cell Transplantation; Cells; Cellular Assay; Clinical Trials; Code; Cytostatics; Cytotoxic Chemotherapy; Data; Endoplasmic Reticulum; FDA approved; GTPase-Activating Proteins; Genes; Goals; Growth; Hereditary Disease; Human; Image; Individual; Language; MEK inhibition; MEKs; Magnetic Resonance Imaging; Maintenance; Malignant Neoplasms; Measures; Mediating; Methods; Modeling; Molecular; Monitor; Mus; Mutation; NF1 gene; Nature; Neurofibromatosis 1; Nude Mice; Oncogenes; Operative Surgical Procedures; Pathway interactions; Patients; Pharmacology; Pharmacotherapy; Phosphotransferases; Play; Plexiform Neurofibroma; Prevention; Principal Investigator; Protein Biosynthesis; Protein Kinase; Proteins; RAS inhibition; RNA; Research Design; Role; Schwann Cells; Signal Pathway; Signal Transduction; Structure; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Tissues; Translating; Ubiquitination; biological adaptation to stress; cytotoxic; cytotoxicity; effective therapy; efficacy testing; endoplasmic reticulum stress; enzyme activity; imaging modality; in vivo; inhibitor; knock-down; mouse model; neoplastic cell; neurofibroma; novel; novel therapeutic intervention; novel therapeutics; phase 1 testing; pre-clinical; preventive intervention; programs; protein degradation; proteostasis; public health relevance; response; ribosome profiling; small hairpin RNA; therapeutic target; transplant model; tumor; tumor growth; tumor initiation; tumorigenesis; valosin-containing protein

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.

主要研究者/项目负责人（末、首、中）：吴建强 使用技术语言，简要描述研究设计和实现既定目标的基本原理 1型神经纤维瘤病（NF 1）是一种遗传性疾病， 称为丛状神经纤维瘤（PNF）的良性雪旺细胞瘤。目前，预防PNF是 这是不可能的，部分原因是肿瘤发生的分子机制尚未完全了解。 手术仍然是治疗PNF的主要手段。FDA批准的细胞抑制MEK抑制剂， Selumetinib（Koselugo）可使70%的个体肿瘤缩小，但停药后肿瘤会重新生长 治疗因此，治疗神经纤维瘤的新的治疗策略和靶点是 迫切需要。内质网（ER）应激反应途径在细胞凋亡中起着关键作用。 肿瘤生长和治疗的几种癌症，但仍然是未经研究的神经纤维瘤。靶向这些 ER应激通路可能为PNF患者提供一种新的治疗方法。 我们的新的初步数据表明：a）所有三种ER应激信号通路都被激活， 与对照组相比，小鼠和人类PNF均如此。B）蛋白激酶RNA样的敲低 内质网激酶（PERK）通过shRNA减少细胞中神经纤维瘤样肿瘤的数量 裸鼠移植模型。c）含缬沙菌素蛋白（VCP）的药理学抑制 与MEK抑制剂（MEKi）一起降低细胞增殖，增加细胞凋亡， 诱导蛋白质泛素化。我们的中心假设是SC/SCP中Nf 1的缺失导致PNF 通过驱动Runx和VCP调节的蛋白质稳态来适应ER应激信号传导， 靶向蛋白质稳态为PNF患者提供了细胞毒性治疗。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， 维持蛋白质稳态，使Nf 1-/- SC/SCP适应ER应激，从而驱动PNF启动， 增长在目标2中，我们将测试是否通过靶向VCP（单独或 与MEKi组合）提供细胞毒性，并因此持久控制PNF生长，并确定 作用机制。 总体而言，本提案将提供Runx 1/3和可能的VCP的机制证据- PNF形成过程中的癌基因依赖性蛋白质稳态和适应性ER应激信号转导 并为MEK非依赖性临床试验提供临床前依据。