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.

项目概要/摘要该补充支持是为非裔美国博士后 Steven Carroll 实验室的 Dorea Jenkins 提供的她是南卡罗来纳医科大学的学者，她的目标是成为一名独立研究员。专注于治疗恶性周围神经鞘瘤（MPNST），该肿瘤具有侵袭性。 1 型神经纤维瘤病 (NF1) 患者和一般人群中偶发发生的肿瘤。由于目前的 Ras 过度激活治疗无效，MPNST 患者的预后很严峻。这是由于编码肿瘤抑制因子神经纤维蛋白的 NF1 缺失所致，这表明 Ras 受到抑制。信号传导将是治疗难以直接靶向的 MPNST 和药物靶向的有效手段。 Ras 信号传导对 MPNST 患者无效，因此我们研究了关键的治疗靶点。我们研究了 58 个 RTK 在 MPNST 中的作用。我们基于 RTK 的药理学筛选证实 erbB 是散发性/NF1 相关的 MPNST 细胞系。抑制剂 canertinib 和 IGF1 受体 (IGF1R) 抑制剂鬼臼苦素抑制 MPNST 生长/Ras 我们的基因组规模 shRNA 筛选也确定了 erbB3 和 IGF1R 对于生长至关重要。 MPNST 细胞的体内生长依赖于 erbB3 和 IGF1R 的作用。同时针对这些关键 RTK 的治疗方案将有效治疗 MPNST 1)。我们将测试以下假设：针对 erbB 受体和 IGF1R 的组合疗法将有效抑制 MPNST 异种移植物体内生长 2) 我们将测试 erbB3 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) 我们将检验药物的假设。复发是由“次级”RTK 介导的，该 RTK 补偿 erbB 和 IGF1R 抑制以驱动关键的细胞质在此应用中，我们提出了一个额外的目标：我们将测试 NRG1β- 的假设。介导的 erbB3 激活促进 CCL2 分泌，从而募集 M2 巨噬细胞，并且雪旺细胞减少 Nf1 基因剂量可增强 CCL2 的分泌和巨噬细胞对 CCL2 的反应。亲本 R01 专注于抑制 MPNST 细胞中的 erbB3 和 IGF1R 信号传导的细胞自主作用，它没有解决 erbB3 激活具有促进 MPNST 的非细胞自主作用的可能性确定 erbB3 促进非肿瘤细胞类型进入肿瘤等发病机制。 MPNST 的发病机制是通过促进招募/激活巨噬细胞的细胞因子的分泌来实现的这项工作将提供结合 erbB3 和 CCL2 抑制的疗法可能对 MPNST 有效。 Jenkins 博士提供了她独立所需的 K22 应用/培训数据。使我们能够开发出针对无法治疗的肉瘤的有效疗法。我们的方法在散发性肿瘤中得到越来越多的认可，在人类癌症中也有更广泛的应用。