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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.!

恶性周围神经鞘肿瘤（MPNSTs）是源自雪旺细胞的侵袭性肿瘤