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：
10436971
负责人：
STEVEN L. CARROLL
金额：
$ 37.77万
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/10436971
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 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 lung Carcinoma 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

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.!

恶性周围神经鞘瘤（MPNST）是源自雪旺细胞的新侵袭性血浆谱系常见于 1 型神经纤维瘤病 (NF1) 患者，也偶发于由于目前的放射治疗和化疗，一般人群的 MPNST 患者的预后很严峻。 Ras 过度激活是由功能性 NF1 丧失引起的，通常发生在这种情况下。与其他肿瘤抑制突变（CDKN2A、TP53 或 SUZ12）组合是 MPNST 的特征。这表明抑制 Ras 信号传导将是治疗 MPNST 的有效手段。已被证明很难直接靶向治疗，并且靶向 Ras 效应通路的药物尚未实现对 MPNST 患者有效，这促使我们研究靶向治疗的有效性。 Ras 的关键上游激活剂，例如 MPNST 中的受体酪氨酸激酶 (RTK)，我们研究了其作用。使用药理学和基因组规模对散发性和 NF1 相关 MPNST 细胞系中的所有 58 个 RTK 进行分析 shRNA 筛选与全面的基因组分析相结合我们基于 RTK 的药理学筛选。确定广谱 ERBB 抑制剂 canertinib 和 IGF1 受体 (IGF1R) 抑制剂鬼臼苦素有效抑制 MPNST 生长和 Ras 激活，与这些结果一致，我们的研究结果如下。基因组规模的 shRNA 筛选确定 ERBB3 和 IGF1R 对于 MPNST 细胞的生长至关重要。基于这些发现，我们认为 MPNST 体内生长依赖于 ERBB3 和 IGF1R 以及同时针对这些关键 RTK 的治疗方案将我们将在三个具体目标中严格检验这一假设。将测试针对 ERBB 受体和 IGF1R 的组合疗法将有效抑制这一假设我们还将确定其他 RTK 是否可重复激活以促进体内 MPNST 异种移植物生长。对 ERBB 和 IGF1R 抑制剂的耐药性和肿瘤复发在具体目标 2 中，我们将测试其体内作用。使用异种移植物和基因工程小鼠模型研究 ERBB3 在肿瘤发生和药物敏感性中的作用 (GEMM)。在具体目标 3 中，我们将检验药物复发是由“次要”RTK 介导的假设，补偿 ERBB 和 IGF1R 抑制以驱动关键的细胞质信号传导途径。因此，该计划将使我们能够为目前无法治疗的肉瘤类型开发有效的疗法。 NF1 突变和 Ras 过度激活在其他散发性肿瘤类型中得到越来越多的认识，我们的研究该方法对许多其他类型的人类癌症有更广泛的应用。！