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

• 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
• 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

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）：多形性胶质母细胞瘤（GBM）仍然是中枢神经系统最具破坏性的恶性肿瘤，过去几十年在治疗开发方面几乎没有取得进展。以广泛生长、广泛血管化和显著的化学抗性为特征，GBM表现出不可避免的复发，并且尽管治疗，仅与14个月的生存预后相关。先前的工作[13]已经确定了一种新的调节途径（氧化还原/Fyn/c-Cbl（RFC））途径，其存在于CNS的祖细胞中，并且似乎在GBM中失调。抑制E3泛素连接酶c-Cbl的正常调节使通过受体酪氨酸激酶（RTK）的促有丝分裂信号传导永久化，并赋予对化疗剂的抗性。假定参与多种细胞内信号传导途径暗示c-Cbl作为介导GBM病理学的整合网络中的潜在汇聚点。初步数据表明，粘着斑激酶（FAK）和热休克蛋白90（HSP 90）都是c-Cbl功能障碍的贡献者，激发了对这些化合物的药理学抑制作为挽救正常c-Cbl调节的手段的研究。因此，在本发明中，该提议旨在测试以下假设：1）FAK的药理学抑制恢复正常c-Cbl功能，并能够实现GBM细胞的治疗相关靶向; 2）HSP 90的药理学抑制也恢复正常c-Cbl活性，从而能够实现GBM细胞的治疗靶向;以及3）FAK和HSP 90的小分子抑制剂恢复c-Cbl活性，Cbl活性并在GBM的人异种移植小鼠模型中表现出治疗相关性。GBM细胞中c-Cbl的遗传敲除和RFC途径的扰动将与在药理学抑制剂和化疗剂存在下蛋白质相互作用、细胞活力、RTK降解和癌症干细胞表型的分析相结合，以测试c-Cbl功能在这些作用中的重要性。我们的总体目标是确定FAK和HSP 90的新作用，并确认c-Cbl抑制在胶质瘤生物学中的重要性，以指导创新疗法的开发。