Project 3: Inhibition of radiation-induced phenotype conversion in glioblastoma

项目3：抑制放射诱导的胶质母细胞瘤表型转换

• 批准号: 9983049
• 负责人: Frank Pajonk
• 金额: $ 35.34万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-11 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9983049
• 关键词: Address; Affect; Allografting; Back; Basic Science; Biology; Cell Differentiation process; Cells; Clinical; Clinical Trials; Clonal Evolution; Combined Modality Therapy; Data; Disease; Dopamine Antagonists; Electromagnetic Energy; Failure; Generations; Glioblastoma; Glioma; Goals; Growth; Hypoxia; In Vitro; Literature; Malignant Neoplasms; Malignant neoplasm of brain; Modality; Modeling; Mus; Nitric Oxide; Operative Surgical Procedures; Outcome; Oxygen; Patient-Focused Outcomes; Patients; Pharmacology; Phenotype; Physiological; Population; Process; Progression-Free Survivals; Publishing; Radiation; Radiation Dose Unit; Radiation Oncology; Radiation Tolerance; Radiation therapy; Recurrence; Reporting; Resources; Solid Neoplasm; Testing; Time; Treatment Failure; Xenograft procedure; base; cancer stem cell; chemoradiation; disorder control; drug development; effective therapy; imaging system; improved; in vivo; individual patient; inhibitor/antagonist; innovation; mouse model; novel; prevent; quetiapine; radiation resistance; radioresistant; small molecule libraries; stem cells; therapy resistant; tool; trait; treatment response; tumor; tumorigenic

Project 3: Inhibition of radiation-induced phenotype conversion in glioblastoma SUMMARY/ABSTRACT Despite a tremendous effort in basic science, clinical trials, drug development, and technical advances in surgery and radiation oncology, glioblastoma remains incurable and improvements in overall survival have been marginal. While radiotherapy is still one of the most effective treatment options for glioblastoma, it cannot control the disease over time. This led us to conclude that novel combination therapies are desperately needed to improve radiation treatment outcome for patients suffering from this disease. The studies outlined in this proposal are based on a hypothesis that is backed by our extensive preliminary data and rigorous published data in the literature. Specifically, we hypothesize that radiation causes a phenotype conversion of differentiated glioma cells into therapy-resistant glioma-initiating cells (GICs), and that interfering with this process will increase the efficiency of radiotherapy. The three aims of this study will address this aspect of glioma biology using an innovative tool to track GICs and their progeny, while leveraging the unique resources and expertise available in the proposed UCLA SPORE in Brain Cancer. In Aim 1, we will study spontaneous and radiation-induced phenotype conversion in glioblastoma under different microenvironmental conditions, and determine if this process generates tumorigenic GICs in vitro and in vivo. In Aim 2, we will attempt to prevent phenotype conversion of non-tumorigenic cells into GICs using dopamine receptor antagonists. Finally, in Aim 3, we propose a novel clinical trial to test whether quetiapine, a dopamine receptor antagonist, can reduce the number of GICs in patients with recurrent GBM and prolong their survival. If successful, results from these studies could have a wider impact on cancer, as these principles may apply not only to glioblastoma but to many other solid tumors.

项目3：抑制胶质母细胞瘤中辐射诱导的表型转化 总结/摘要 尽管在基础科学、临床试验、药物开发和技术进步方面做出了巨大努力， 手术和放射肿瘤学，胶质母细胞瘤仍然是不可治愈的，总生存率的改善 边缘化。虽然放射治疗仍然是胶质母细胞瘤最有效的治疗选择之一，但它不能 随着时间的推移控制疾病。这使我们得出结论，迫切需要新的联合疗法 以改善患有这种疾病的患者的放射治疗结果。本文中概述的研究 我们的建议是基于一个假设，这是由我们广泛的初步数据和严格的出版支持。 文献中的数据。具体地说，我们假设辐射引起表型转换， 将神经胶质瘤细胞分化为治疗抗性神经胶质瘤起始细胞（GIC）， 这将提高放射治疗的效率。本研究的三个目标将解决这方面的问题， 神经胶质瘤生物学使用创新工具跟踪GIC及其后代，同时利用独特的资源 和专业知识可在拟议中的加州大学洛杉矶分校孢子在脑癌。在目标1中，我们将研究自发性 和不同微环境条件下胶质母细胞瘤中辐射诱导的表型转化， 并确定该过程是否在体外和体内产生致瘤性GIC。在目标2中，我们将尝试 使用多巴胺受体拮抗剂防止非致瘤细胞表型转化为GIC。 最后，在目标3中，我们提出了一项新的临床试验，以测试多巴胺受体拮抗剂奎替利， 可减少复发性GBM患者的GIC数量，延长其生存期。如果成功，结果 这些研究可能对癌症产生更广泛的影响，因为这些原则不仅适用于 胶质母细胞瘤也适用于许多其他实体瘤。