Identifying c-Cbl as a critical point of intervention in glioblastoma multiforme

将 c-Cbl 确定为多形性胶质母细胞瘤干预的关键点

基本信息

批准号：
8521532
负责人：
Jennifer Lynn Stripay
金额：
$ 4.22万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8521532
关键词：
Biology Brain Cell Line Cell Survival Cells Characteristics Classification Co-Immunoprecipitations Combined Modality Therapy Data Dependency Development Diagnosis Dose Epidermal Growth Factor Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Excision Exhibits Focal Adhesion Kinase 1 Functional disorder Genetic Glioblastoma Glioma Goals Growth HSP 90 inhibition Heat-Shock Proteins 90 Human Immigration In Vitro Intervention Investigation Maintenance Malignant Neoplasms Malignant neoplasm of central nervous system Mediating Mediator of activation protein Mutation Neuraxis Normal Cell Operative Surgical Procedures Outcome Oxidation-Reduction Oxidative Stress Pathology Pathway interactions Patients Phenotype Phosphorylation Phosphotransferases Preclinical Drug Evaluation Primary Brain Neoplasms Property Protein Analysis RNA Interference Radiation therapy Receptor Protein-Tyrosine Kinases Recurrence Regulation Regulatory Pathway Resistance Role Signal Pathway Signal Transduction Site Stem Cell Development Stem cells Surface Testing Therapeutic Therapeutic Intervention Transplantation Tyrosine Phosphorylation Ubiquitination Vascularization Western Blotting Work World Health Organization Xenograft procedure base betaPIX protein cancer cell cancer stem cell chemotherapeutic agent chemotherapy in vivo inhibitor/antagonist innovation interest kinase inhibitor knock-down mouse model novel outcome forecast prevent public health relevance response restoration small molecule success therapeutic development tumor tumor growth ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) remains the most devastating malignancy of the central nervous system, with little progress having been made over the last several decades in terms of therapeutic development. Characterized by pervasive growth, extensive vascularization and marked chemoresistance, GBM exhibits inevitable recurrence and despite treatment, is associated with only a 14-month survival prognosis. Previous work [13] has identified a novel regulatory pathway (the redox/Fyn/c-Cbl (RFC)) pathway that is present in progenitor cells of the CNS, and appears to be dysregulated in GBM. Inhibiting normal regulation of the E3 ubiquitin ligase c-Cbl perpetuates pro-mitogenic signaling through receptor tyrosine kinases (RTKs), and confers resistance against chemotherapeutic agents. Putative involvement in a multitude of intracellular signaling pathways implicates c-Cbl as a potential convergence point in an integrated network mediating GBM pathology. Preliminary data suggest focal adhesion kinase (FAK) and heat shock protein 90 (HSP90) both are contributors to c-Cbl dysfunction, motivating an investigation into pharmacological inhibition of these compounds as a means of rescuing normal c-Cbl regulation. As such, this proposal aims to test the hypotheses that 1) pharmacological inhibition of FAK restores normal c-Cbl function and enables therapeutically relevant targeting of GBM cells 2) pharmacological inhibition of HSP90 also restores normal c-Cbl activity to enable therapeutical targeting of GBM cells and 3) small molecule inhibitors of FAK and HSP90 restore c-Cbl activity and exhibit therapeutic relevance in a human xenograft mouse model of GBM. Genetic knockdown of c-Cbl and perturbation of the RFC pathway in GBM cells will be combined with analysis of protein interactions, cell viability, RTK degradation, and cancer stem cell phenotype in the presence of pharmacological inhibitors and chemotherapeutics to test the importance of c-Cbl function in these effects. Our overarching goal is to identify novel roles for both FAK and HSP90 and confirm the importance of c-Cbl inhibition in glioma biology to guide development of innovative therapeutics.

描述（由申请人提供）：胶质母细胞瘤多形（GBM）仍然是中枢神经系统中最具破坏性的恶性肿瘤，在过去几十年中，在治疗性发育方面几乎没有取得进展。 GBM以普遍的生长，广泛的血管化和明显的化学抗性为特征，尽管不可避免地复发，并且仅处理了14个月的生存预后。先前的工作[13]已经确定了一种新型的调节途径（氧化还原/fyn/c-CBL（RFC））途径，该途径存在于CNS的祖细胞中，并且在GBM中似乎失调。抑制E3泛素连接酶C-CBL的正常调节，可以通过受体酪氨酸激酶（RTKS）促进有效信号，并赋予对化学治疗剂的耐药性。推定参与多种细胞内信号通路将C-CBL视为综合网络介导GBM病理学的潜在收敛点。初步数据表明局部粘附激酶（FAK）和热休克蛋白90（HSP90）都是C-CBL功能障碍的促进者，激励研究这些化合物的药理抑制作用，以作为挽救正常C-CBBL调节的一种手段。 As such, this proposal aims to test the hypotheses that 1) pharmacological inhibition of FAK restores normal c-Cbl function and enables therapeutically relevant targeting of GBM cells 2) pharmacological inhibition of HSP90 also restores normal c-Cbl activity to enable therapeutical targeting of GBM cells and 3) small molecule inhibitors of FAK and HSP90 restore c-Cbl activity and exhibit therapeutic与GBM的人异种移植小鼠模型相关。 C-CBL的遗传敲低和GBM细胞中RFC途径的扰动将与蛋白质相互作用，细胞活力，RTK降解和癌症干细胞表型的分析相结合，在药理学抑制剂和化学治疗学的存在下，以测试C-CBL在这些作用中的重要性。我们的总体目标是确定FAK和HSP90的新作用，并确认C-CBL抑制在神经胶质瘤生物学中的重要性，以指导创新疗法的发展。