Cooperating pathways in glioblastoma stem cells

胶质母细胞瘤干细胞的合作途径

• 批准号: 9552319
• 负责人: Jeongwu Lee
• 金额: $ 40万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9552319
• 关键词: Agonist; Alpha Cell; Antipsychotic Agents; Automobile Driving; Binding Sites; Biological Markers; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Cell Maintenance; Cells; Cellular biology; Clinic; Clinical; Computer Simulation; Coupled; Data; Development; Dopamine; Dopamine Receptor; Drug Delivery Systems; Epidermal Growth Factor Receptor; Equilibrium; Excision; FDA approved; G-substrate; GTP-Binding Proteins; Genetic; Glioblastoma; Glioma; Growth; Heterotrimeric GTP-Binding Proteins; Hyperactive behavior; In Vitro; Knock-out; Lead; Ligands; Link; Malignant Neoplasms; Malignant neoplasm of brain; Maps; Mediating; Modeling; Molecular; Molecular Target; Neurotransmitters; Oncogenic; Operative Surgical Procedures; PDGFRB gene; Pathway interactions; Patients; Peptides; Perphenazine; Pharmaceutical Preparations; Pharmacology; Phenotype; Play; Primary Brain Neoplasms; Protein Analysis; Radiation; Radioresistance; Reagent; Receptor Protein-Tyrosine Kinases; Resistance; Role; STAT3 gene; Signal Pathway; Signal Transduction; Specimen; Stem cells; Testing; Therapeutic; Translations; Treatment Efficacy; Treatment Failure; Tumorigenicity; Xenograft Model; Xenograft procedure; antitumor effect; base; brain tissue; cancer stem cell; cell growth; chemotherapy; conventional therapy; design; improved; in vivo; inhibitor/antagonist; irradiation; knock-down; neoplastic cell; novel; pre-clinical; predictive marker; radioresistant; self-renewal; standard care; stem; systemic toxicity; targeted agent; targeted treatment; temozolomide; therapeutic evaluation; therapeutic target; treatment response; tumor; tumor growth; tumor heterogeneity; tumor progression; tumorigenic; validation studies

ABSTRACT Glioblastoma (GBM) is the most common and the most lethal brain cancer. Unfortunately, there has been tragically little therapeutic progress over the last 30 years. Surgery provides modest benefit, the blood-brain barrier (BBB) limits drug access, and GBM cells are resistant to radiation and to the leading chemotherapy, temozolomide. Targeted therapies for GBM have yielded disappointing results in trials to date. The challenges inherent in developing effective GBM therapeutic approaches have become increasingly clear, and include resistance to standard treatments, drug delivery into the tumor, a subpopulation of stem-like GBM cells (GSCs), and genetic complexity and molecular adaptability of GBM. GBM tumors display a cellular hierarchy of differentiation states, in which GSCs maintain a dynamic balance between the state of self-renewal and differentiation. A myriad of molecular signaling pathways crucial for the normal brain development also play important roles in glioma initiation and progression. We previously demonstrated that MET receptor tyrosine kinase signaling is a crucial regulator of GSCs. Recent studies have implicated that various neurotransmitter signaling can promote tumor growth and progression via maintaining stem cell state. Our recent studies and preliminary data have discovered that dopamine receptor subtype 2 (DRD2), a key receptor of dopamine signaling, promoted GBM growth via regulating the stem cell state of GSCs. Unexpectedly, DRD2 was highly expressed in clinical GBM specimens, with preferential expression in GSCs, compared to normal brain tissue. Mechanistically, DRD2 facilitated proliferation and clonogenic growth of GBM cells via activation of MET. This finding is highly relevant because MET signaling is frequently hyperactive in GBMs as a key regulator of cancer stem phenotype and GBM radio-resistance, and it is a well-recognized therapeutic target in GBM. Importantly, DRD2 knockdown or an FDA-approved DRD2 antagonist-mediated DRD2 inhibition potently inactivated oncogenic signaling pathways, diminished clonogenic growth of GSCs, and impeded GBM growth in orthotopic xenograft models. Furthermore, we found a strong synergistic anti- tumor effect by combination of MET inhibitor and DRD2 antagonist in a subset of GBM. This project will interrogate the roles of MET-DRD2 signaling in GSC self-renewal and GBM progression, and elucidate the mechanisms of oncogenic DRD2 signaling at the molecular level (Aim 1), and test therapeutic efficacy of FDA- approved antipsychotic drugs and novel inhibitory peptides that can specifically block the interaction between DRD2 and MET (Aim 2), and determine therapeutic efficacies of these targeting reagents alone or in combination with standard therapies in preclinical patient GBM-derived orthotopic tumor models and identify the biomarkers that predict therapeutic response (Aim 3). We anticipate that completion of these proposed studies will yield a new paradigm for cancer stem cell biology and provide a novel and effective therapeutic approach, which may lead to the translation into improved therapies.

摘要 胶质母细胞瘤(GBM)是最常见和最致命的脑癌。不幸的是，已经有了 可悲的是，在过去的30年里，治疗进展甚微。手术提供了适度的好处，血脑 屏障(BBB)限制了药物的获取，而GBM细胞对放射和主要化疗具有抵抗力， 替莫唑胺。到目前为止，针对GBM的靶向治疗在试验中取得了令人失望的结果。挑战 开发有效的GBM治疗方法所固有的已经变得越来越清楚，包括 对标准治疗的抗药性、向肿瘤内的药物输送、干细胞样基底膜细胞亚群 (GSCs)、遗传复杂性和分子适应性。 GBM肿瘤表现出分化状态的细胞层次结构，其中GSCs维持动态平衡 在自我更新和差异化之间。无数的分子信号通路对 正常的脑发育在胶质瘤的发生和发展中也起着重要的作用。我们之前 证明MET受体酪氨酸激酶信号转导是GSCs的重要调节因子。最近的研究表明 提示多种神经递质信号通过维持多种神经递质信号促进肿瘤的生长和发展 干细胞状态。 我们最近的研究和初步数据发现，多巴胺受体亚型2(DRD2)是一个关键的 多巴胺信号受体，通过调节GSCs的干细胞状态促进GBM的生长。 出乎意料的是，DRD2在临床GBM标本中高度表达，并优先在GSC中表达， 与正常脑组织相比。从机制上讲，DRD2促进了GBM的增殖和克隆生长 通过激活MET激活细胞。这一发现是高度相关的，因为MET信号经常在 GBMS作为肿瘤干细胞表型和GBM辐射抗性的关键调节因子，是公认的 基底膜的治疗靶点。重要的是，DRD2基因敲除或FDA批准的DRD2拮抗剂介导 DRD2抑制有效地灭活了致癌信号通路，减少了GSC的克隆生长， 并抑制异种原位移植模型中GBM的生长。此外，我们还发现了一种很强的协同抗- MET抑制剂和DRD2拮抗剂联合应用对GBM亚群的肿瘤效应。这个项目将 探讨MET-DRD2信号在GSC自我更新和GBM进展中的作用，并阐明MET-DRD2信号在GSC自我更新和GBM进程中的作用 致癌DRD2信号在分子水平的机制(目标1)，并测试FDA-1的治疗效果 已批准的抗精神病药物和可特异性阻断相互作用的新型抑制肽 DRD2和MET(目标2)，并确定这些靶向试剂单独或在 临床前患者GBM来源的原位肿瘤模型与标准治疗的联合应用 预测治疗反应的生物标志物(目标3)。我们预计这些拟议工作将完成 研究将为癌症干细胞生物学提供一个新的范例，并提供一种新的有效的治疗方法 方法，这可能导致转化为改进的治疗方法。