The Role of HER3 and IGF1R, through Non-Classical Ras Signaling, on Malignant Peripheral Nerve Sheath Tumor Progression

HER3 和 IGF1R 通过非经典 Ras 信号传导对恶性周围神经鞘肿瘤进展的作用

• 批准号: 10540687
• 负责人: Shannon Weber Doutt
• 金额: $ 3.33万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10540687
• 关键词: Ablation; Affect; Automobile Driving; Biological Process; Canertinib; Cell Lineage; Cell Survival; Cells; Chemotherapy and/or radiation; Clustered Regularly Interspaced Short Palindromic Repeats; Combined Modality Therapy; Common Neoplasm; Compensation; Coupled; Data; Disease; Dominant-Negative Mutation; ERBB3 gene; Event; Excision; Family; Family member; Feedback; Genetic Screening; Growth; Image; Immunodeficient Mouse; In Vitro; Individual; Insulin-Like-Growth Factor I Receptor; Invaded; KRAS2 gene; Knock-out; Laboratories; Link; Luciferases; MEKs; Migration Assay; NF1 gene; Neoplasm Metastasis; Nerve; Neurofibromatosis 1; Neurofibrosarcoma; Operative Surgical Procedures; PI3K/AKT; PIK3CG gene; Pathway interactions; Patients; Phenotype; Phosphorylation; Phosphotransferases; Process; Prognosis; Proliferating; Protein Isoforms; Proteins; R-ras protein; RAS driven cancer; Receptor Protein-Tyrosine Kinases; Recurrence; Role; Schwann Cells; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Soft tissue sarcoma; Spindle Cell Neoplasm; Testing; Therapeutic; Tumor Cell Invasion; Tumor Cell Line; Validation; Western Blotting; Xenograft procedure; combinatorial; drug sensitivity; effective therapy; established cell line; experimental study; expression vector; imaging system; in vivo; inhibitor; live cell imaging; migration; neoplastic cell; novel; novel strategies; pharmacologic; ras Proteins; receptor; receptor expression; sarcoma; targeted treatment; therapeutic target; three dimensional cell culture; tumor; tumor growth; tumor progression; tumor xenograft

PROJECT SUMMARY/ABSTRACT  Currently, no effective treatment for Malignant Peripheral Nerve Sheath Tumors (MPNSTs) exists outside of radical resection, which has poor long-term survival, putting patients with this aggressive spindle cell neoplasm in dire need of an effective treatment. Loss of Neurofibromin 1 (NF1) and subsequent Ras activation are hallmarks of this disease. Proposed therapies targeting Ras and its downstream effectors have failed, so we are exploring targeting upstream activators of Ras, specifically Receptor Tyrosine Kinases (RTKs), which are activated in a positive feedback loop as a result of NF1 loss. Using pharmacologic and genetic screens, we assessed the contribution of all 58 RTKs in MPNST proliferation and survival, identifying the HER receptor HER3 and Insulin-like Growth Factor 1 Receptor (IGF1R) as critical for MPNST progression. Subsequent validation experiments with the broad spectrum HER inhibitor canertinib and an IGF1R inhibitor, picropodophylin (PPP), showed a decrease in proliferation of MPNST cells, with a statistically significant decrease in cell viability with combination treatment. Levels of activated Ras and phosphorylated Erk1/2 were also reduced following combinatorial treatment. While our preliminary data show a decrease in proliferation of MPNST cells and reduced expression of IGF1R initially after HER3 ablation, we observe that in late passage cells, there is a subsequent increase in IGF1R expression and a rescue in proliferation, suggesting compensation and cooperation between the two RTKs. Our preliminary studies also link HER3 to R-Ras family member proteins, specifically linking loss of HER3 with reduced activation of activated R-Ras and R-Ras2. We have explored the role of R-Ras in MPNST migration and invasion, finding a decrease in migration and loss of invasive phenotype after loss of R-Ras family members (via dominant negative vector expression). We propose to rigorously test the hypothesis that HER3 and IGF1R cooperatively promote MPNST progression and modulate migration and invasion through isoform-specific activation of R-Ras proteins and downstream signal transduction pathways of Raf/MEK/ERK and PI3K/AKT; this will be accomplished through 2 aims: first, examining the cooperation of HER3 and IGF1R as activators of Ras isoforms to drive proliferation, migration and invasion, and secondly by testing combinatorial therapy with HER3 and IGF1R inhibitors as a novel approach to effectively inhibit tumor growth when compared to monotherapy with either agent alone. We hope to elucidate the mechanism of RTKs and Ras isoforms on MPNST progression, coupled with identifying a novel combinatorial therapeutic strategy for those suffering from this and other NF1 driven diseases.

项目总结/文摘