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Therapeutic Targeting of Receptor Tyrosine Kinase Hierarchies in Schwann Cell Neoplasms - Supplement for Diversity

雪旺细胞肿瘤中受体酪氨酸激酶层次结构的治疗靶向 - 多样性补充

基本信息

批准号：
10527086
负责人：
STEVEN L. CARROLL
金额：
$ 11.73万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10527086
关键词：
1-Phosphatidylinositol 3-Kinase Ablation Address African American Antibodies Apoptosis Automobile Driving Biological Assay Breast Carcinoma CCL2 gene Canertinib Cause of Death Cell Death Cell Line Cell Lineage Cell Proliferation Cell secretion Cells Clinical Coupled Data Dose Drug Targeting Drug resistance EGFR gene ERBB3 gene Effectiveness Gene Dosage General Population Genetic Diseases Genetically Engineered Mouse Genomics Glioblastoma Goals Growth Human IGF1 gene Immunocompetent In Vitro Individual MAP Kinase Gene Malignant Neoplasms Mediating Medical Methods Mutation NF1 gene Neoplasms Neurofibromatosis 1 Neurofibrosarcoma Outcome PI3K/AKT Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phenotype Radiation Radiation therapy Radio Receptor Inhibition Receptor Protein-Tyrosine Kinases Receptor Signaling Recurrence Regimen Relapse Research Personnel Resistance Role Schwann Cells Signal Pathway Signal Transduction Site South Carolina Testing Therapeutic Training Tumor Cell Line Tumor Subtype Tumor Suppressor Genes Tumor Suppressor Proteins Tumor Tissue Universities Work Xenograft procedure base cell type combinatorial cytokine design drug candidate drug relapse drug sensitivity effective therapy effectiveness evaluation genome-wide hyperactive Ras in vivo in vivo evaluation inhibitor lung Carcinoma macrophage melanoma neoplastic cell overexpression patient prognosis receptor recruit response sarcoma small hairpin RNA small molecule targeted agent targeted treatment therapeutic effectiveness therapeutic target tumor tumor growth tumor initiation tumor xenograft tumorigenesis

项目摘要

PROJECT SUMMARY/ABSTRACT This supplement support is for Dorea Jenkins in the lab of Steven Carroll, an African-American postdoctoral scholar at the Medical University of South Carolina. Her goal is to become an independent researcher. Our R01 focuses on therapies to treat malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are aggressive neoplasms that occur in patients with neurofibromatosis type 1 (NF1) and sporadically in the general population. The prognosis for patients with an MPNST is grim as current therapeutics are ineffective. Ras hyperactivation, results from loss of NF1 that encodes the tumor suppressor, neurofibromin. This suggests that inhibiting Ras signaling would be an effective means of treating MPNSTs. Ras is difficult to directly target and drugs targeting Ras signaling is not effective in patients with MPNSTs. Therefore, we investigate therapeutically targeting key upstream activators of Ras, receptor tyrosine kinases (RTKs) in MPNSTs. We examined the role of 58 RTKs in sporadic/NF1-associated MPNST cell lines. Our RTK-based pharmacologic screens established that the erbB inhibitor canertinib and the IGF1 receptor (IGF1R) inhibitor picropodophyllin inhibited MPNST growth/Ras activation. Our genome-scale shRNA screens also established erbB3 and IGF1R as essential for the growth of MPNST cells. We hypothesize that MPNST growth in vivo is dependent on the action of erbB3 and IGF1R and that therapeutic regimens simultaneously targeting these key RTKs will effectively treat MPNSTs. 1) We will test the hypothesis that combinatorial therapies targeting erbB receptors and IGF1R will effectively inhibit MPNST xenograft growth in vivo. 2) We will test the in vivo role of erbB3 in tumor initiation and drug sensitivity using xenografts and a genetically engineered mouse model (GEMM). 3) We will test the hypothesis that drug relapse is mediated by “secondary” RTKs that compensate for erbB and IGF1R inhibition to drive key cytoplasmic signaling pathways. In this application, we propose an additional aim: We will test the hypothesis that NRG1β- mediated erbB3 activation promotes CCL2 secretion, which recruits M2 macrophages, and that Schwann cell secretion of CCL2 and macrophage responses to CCL2 are enhanced by decreased Nf1 gene dosage. The parental R01 focuses on the cell-autonomous role of inhibiting erbB3 and IGF1R signaling in MPNST cells, it does not address the possibility that erbB3 activation has non-cell autonomous actions that promote MPNST pathogenesis such as recruiting non-neoplastic cell types into the tumor. Establishing that erbB3 promotes MPNST pathogenesis by promoting the secretion of cytokines that recruit/activate macrophages would suggest that therapies combining erbB3 and CCL2 inhibition might be effective against MPNSTs. This work will provide Dr. Jenkins with data for her K22 application/training necessary for independence. This experimental plan will allow us to develop effective therapies for untreatable sarcomas. As NF1 mutations/Ras hyperactivation are increasingly recognized in sporadic tumors, our approach has broader application in human cancers.

项目总结/摘要这个补充支持是为多雷亚詹金斯在实验室的史蒂芬卡罗尔，非洲裔美国博士后他是南卡罗来纳州医科大学的学者。她的目标是成为一名独立的研究员。R01 专注于治疗恶性外周神经鞘瘤（MPNSTs）的疗法。MPNST具有攻击性 1型神经纤维瘤病（NF 1）患者中发生的肿瘤，在一般人群中偶尔发生。 MPNST患者的预后是严峻的，因为目前的治疗方法无效。Ras过度激活，这是由于编码肿瘤抑制因子神经纤维蛋白的NF 1的丢失。这表明抑制Ras 信号传导将是治疗MPNST的有效手段。Ras难以直接靶向和药物靶向 Ras信号在MPNST患者中无效。因此，我们研究治疗靶向的关键， Ras的上游激活剂，MPNST中的受体酪氨酸激酶（RTK）。我们研究了58个RTK在散发性/NF 1相关MPNST细胞系。我们基于RTK的药理学筛选确定erbB 抑制剂canertinib和IGF 1受体（IGF 1 R）抑制剂苦鬼臼脂素抑制MPNST生长/Ras activation.我们的基因组规模的shRNA筛选也确定了erbB 3和IGF 1 R是生长所必需的。 MPNST细胞我们假设MPNST在体内的生长依赖于erbB 3和IGF 1 R的作用，同时靶向这些关键RTK的治疗方案将有效治疗MPNST。第一章我们将检验以erbB受体和IGF 1 R为靶点的联合疗法将有效抑制体内MPNST异种移植物生长。2)我们将测试erbB 3在肿瘤发生和药物敏感性中的体内作用。使用异种移植物和基因工程小鼠模型（GEMM）。3)我们将检验药物复发是由“次级”RTK介导的，其补偿erbB和IGF 1 R抑制，以驱动关键的细胞质信号通路在本申请中，我们提出了一个额外的目标：我们将测试NRG 1 β- 介导的erbB 3活化促进CCL 2分泌，CCL 2募集M2巨噬细胞， CCL 2的分泌和巨噬细胞对CCL 2的应答通过降低Nf 1基因剂量而增强。的亲本R 01集中在MPNST细胞中抑制erbB 3和IGF 1 R信号传导的细胞自主作用，没有解决erbB 3激活具有促进MPNST的非细胞自主行为的可能性发病机制，如募集非肿瘤细胞类型进入肿瘤。确定erbB 3促进 MPNST的发病机制是通过促进细胞因子的分泌来招募/激活巨噬细胞，这表明 erbB 3和CCL 2抑制联合治疗可能对MPNST有效。这项工作将提供博士Jenkins为她的K22应用程序/独立所需的培训提供数据。该实验计划将使我们能够开发出治疗无法治愈的肉瘤的有效疗法。由于NF 1突变/Ras过度活化是随着在散发性肿瘤中的应用越来越多，我们的方法在人类癌症中具有更广泛的应用。