Therapeutic Targeting of Receptor Tyrosine Kinase Hierarchies in Schwann Cell Neoplasms

雪旺细胞肿瘤中受体酪氨酸激酶层次结构的治疗靶向

基本信息

批准号：
10249969
负责人：
STEVEN L. CARROLL
金额：
$ 37.63万
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/10249969
关键词：
1-Phosphatidylinositol 3-Kinase Ablation Address Antibodies Apoptosis Automobile Driving Biological Assay Breast Carcinoma CDKN2A gene Canertinib Cause of Death Cell Death Cell Line Cell Lineage Cell Proliferation Characteristics Clinical Coupled Dose Drug Targeting Drug resistance EGFR gene ERBB3 gene Effectiveness General Population Genetic Diseases Genetically Engineered Mouse Genomics Glioblastoma Growth Human IGF1 gene Immunocompetent In Vitro Individual MAP Kinase Gene Malignant Neoplasms Mediating Methods Mutation Neoplasms Neurofibromatosis 1 Neurofibrosarcoma Outcome PI3K/AKT Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phenotype Prognosis Radiation Radiation therapy Radio Receptor Inhibition Receptor Protein-Tyrosine Kinases Receptor Signaling Recurrence Regimen Relapse Resistance Role Schwann Cells Signal Pathway Signal Transduction Site Suppressor Mutations TP53 gene Testing Therapeutic Tumor Cell Line Tumor Subtype Tumor Suppressor Genes Tumor Suppressor Proteins Tumor Tissue Xenograft procedure base combinatorial design drug candidate drug relapse drug sensitivity effective therapy effectiveness evaluation functional loss genome-wide hyperactive Ras in vivo in vivo evaluation inhibitor/antagonist lung Carcinoma melanoma neoplastic cell overexpression 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

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive neoplasms derived from the Schwann cell lineage that occur commonly in patients with neurofibromatosis type 1 (NF1) as well as sporadically in the general population. The prognosis for patients with an MPNST is grim, as current radio- and chemo- therapeutic regimens are ineffective. Ras hyperactivation, which results from loss of functional NF1, typically in combination with other tumor suppressor mutations (CDKN2A, TP53, or SUZ12), is characteristic of MPNSTs. This suggests that inhibiting Ras signaling would be an effective means of treating MPNSTs. However, Ras has proven to be difficult to directly target therapeutically and drugs targeting Ras effector pathways have not been effective in patients with MPNSTs. This led us to investigate the effectiveness of therapeutically targeting key upstream activators of Ras, such as receptor tyrosine kinases (RTKs) in MPNSTs. We examined the role of all 58 RTKs in sporadic and NF1-associated MPNST cell lines using both pharmacologic and genome-scale shRNA screens coupled with comprehensive genomic analyses. Our RTK-based pharmacologic screens established that the broad-spectrum ERBB inhibitor canertinib and the IGF1 receptor (IGF1R) inhibitor picropodophyllin effectively inhibited MPNST growth and Ras activation. In keeping with these results, our genome-scale shRNA screens established ERBB3 and IGF1R as essential for the growth of MPNST cells. Based on these findings, 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. We will rigorously test this hypothesis in three Specific Aims. In Specific Aim 1, we will test the hypothesis that combinatorial therapies targeting ERBB receptors and IGF1R will effectively inhibit MPNST xenograft growth in vivo. We will also determine if other RTKs are reproducibly activated to promote resistance to ERBB and IGF1R inhibitors and tumor recurrence. In Specific Aim 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). In Specific Aim 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. This experimental plan will thus allow us to logically develop effective therapies for a currently untreatable type of sarcoma. As NF1 mutations and Ras hyperactivation are increasingly recognized in other sporadic tumor types, our approach has broader application to many other types of human cancers.!

恶性外周神经鞘肿瘤（MPNST）是源自Schwann细胞的侵袭性肿瘤谱系通常发生在1型神经纤维瘤病患者（NF1）的患者中一般人口。 MPNST患者的预后是严峻的，因为目前的放射线和化学疗法治疗方案无效。 RAS过度激活是由于功能NF1的丧失而导致的，通常在与其他肿瘤抑制突变（CDKN2A，TP53或SUZ12）的结合是MPNST的特征。这表明抑制RAS信号将是治疗MPNST的有效手段。但是，拉斯事实证明，很难直接以治疗为目标，靶向RAS效应途径的药物尚未对MPNST患者有效。这使我们研究了历史上的目标的有效性 RA的关键上游激活剂，例如MPNST中的受体酪氨酸激酶（RTK）。我们检查了角色使用药理学和基因组规模 shRNA筛选以及全面的基因组分析。我们的基于RTK的药学屏幕确定广谱ERBB抑制剂canertinib和IGF1受体（IGF1R）抑制剂 picropodophophlillin有效抑制了MPNST生长和RAS激活。为了与这些结果保持一致基因组规模的shRNA筛选建立了ERBB3和IGF1R，对MPNST细胞的生长至关重要。基于这些发现，我们假设体内MPNST生长取决于 ERBB3和IGF1R以及仅针对这些关键RTK的治疗方案将有效治疗MPNST。我们将以三个特定目标严格检验这一假设。在特定目标1中，我们将检验以下假设，即针对ERBB受体和IGF1R的组合疗法将有效抑制体内MPNST Xenographic增长。我们还将确定其他RTK是否被重复激活以促进对ERBB和IGF1R抑制剂和肿瘤复发的抗性。在特定目标2中，我们将测试体内角色 ERBB3在肿瘤起始和药物敏感性中使用Xenographtics和基因工程的小鼠模型（宝石）。在特定目标3中，我们将检验以下假设：药物继电器是由“次级” RTK介导的，补偿ERBB和IGF1R抑制，以驱动键的细胞质信号通路。这个实验因此，计划将使我们能够为当前不可治疗的肉瘤开发有效的疗法。作为在其他零星肿瘤类型中，NF1突变和RAS过度激活越来越多地认识到我们方法对许多其他类型的人类癌症具有更广泛的应用。