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

基本信息

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
项目类别：
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

项目摘要

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：抑制放射诱导的胶质母细胞瘤表型转化摘要/摘要尽管在基础科学、临床试验、药物开发和技术进步方面付出了巨大努力手术和放射肿瘤学，胶质母细胞瘤仍然无法治愈，总体生存率有所改善已被边缘化。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改善患有这种疾病的患者的放射治疗结果。本文概述的研究提案基于一个假设，该假设得到我们广泛的初步数据和严格发表的数据的支持文献中的数据。具体来说，我们假设辐射导致表型转变神经胶质瘤细胞分化为治疗抵抗性神经胶质瘤起始细胞（GIC），并且干扰这种细胞过程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追踪 GIC 及其后代，同时利用独特的资源以及拟议的 UCLA SPORE 脑癌中可用的专业知识。在目标 1 中，我们将研究自发性以及不同微环境条件下胶质母细胞瘤辐射诱导的表型转换，并确定该过程是否在体外和体内产生致瘤 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来测试喹硫平（一种多巴胺受体拮抗剂）是否可以减少复发性 GBM 患者的 GIC 数量并延长其生存期。如果成功的话结果这些研究可能会对癌症产生更广泛的影响，因为这些原则可能不仅适用于胶质母细胞瘤也适用于许多其他实体瘤。