Microenvironmental regulation of glioblastoma radiosensitivity

胶质母细胞瘤放射敏感性的微环境调节

• 批准号: 7778520
• 负责人: Philip Tofilon
• 金额: $ 34.65万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7778520
• 关键词: Accounting; Adherent Culture; Apoptosis; Brain; Cell Cycle Arrest; Cell Line; Cells; Clinical Trials; Data; Diagnosis; Disease; Environment; Gene Expression; Gene Expression Profile; Genes; Genotype; Glioblastoma; Goals; Growth; Heterogeneity; Human; In Situ; In Vitro; Investigation; Laboratories; Leg; Mediating; Modification; Molecular; Molecular Profiling; Normal tissue morphology; Patients; Pattern; Phenotype; Polyribosomes; Process; Proteins; Protocols documentation; RNA; RNA Binding; Radiation; Radiation Tolerance; Radiation therapy; Radiation-Induced Gene Expression; Radiosensitization; Regulation; Simulate; Testing; Translations; Tumor Cell Line; Xenograft Model; Xenograft procedure; base; cell type; design; established cell line; genome-wide; improved; in vivo; insight; neglect; neoplastic cell; novel; novel strategies; pre-clinical; public health relevance; tumor; tumor growth; tumor xenograft

DESCRIPTION (provided by applicant): Whereas radiotherapy significantly prolongs the survival of patients with glioblastoma (GB), the vast majority succumb to disease within 1-2 years of diagnosis. The overall goal of this proposal is to delineate the molecules and processes that contribute to the radioresistance of GB. Traditionally, laboratory investigations of human GB radioresponse have primarily focused on tumor cell lines grown in monolayer culture and/or as leg tumor xenografts, in essence neglecting the impact of the normal brain milieu. However, our initial data indicate that intracerebral growth of established GB cell lines alters their basal and radiation-induced gene expression profiles. The overriding premise of this proposal is that the brain microenvironment has a determining impact on GB radioresponse; thus to understand the mechanisms mediating GB radioresistance it will be necessary to account for its unique in situ circumstances. Towards this end, the proposed studies will focus on intracerebral xenografts grown from CD133+ GB tumor initiating cells (TICs). In contrast to established cell lines, intracerebral xenografts grown from TICs replicate the genotype/phenotype and in vivo growth pattern of primary GBs; such xenografts are then also likely to best simulate the consequences of the brain microenvironment on GB radioresponse. The proposed studies will involve 3 Aims. The first aim will define the influence of orthotopic growth on the basal and radiation-induced gene expression profiles of GB TICs. These studies will involve microarray-based transcriptome and gene translation analyses of GB TICs grown in vitro and in vivo as leg tumor and intracerebral xenografts. These genome-wide interrogations will test the hypothesis that the orthotopic environment uniquely influences GB TIC gene expression. Along these lines, an additional hypothesis to be tested is that the radioresponse of GB TICs includes proteins uniquely expressed or induced under intracerebral conditions. The second aim will determine whether the radioresponse of cells within a TIC intracerebral xenograft differ according to topology and/or phenotype. These studies will test the hypothesis that the intra-tumor heterogeneity generated by orthotopic growth results in subpopulations with varying degrees of radiosensitivity. Finally, the third aim is to test the hypothesis that there are targets for GB radiosensitization unique to the orthotopic environment. Studies will initially define the ability of single and fractionated radiation protocols to control the growth of TIC intracerebral xenograft. Targeted strategies suggested from Aims 1 and 2 will then be tested for their ability to enhance radiation-induced growth control. It is anticipated that these studies will generate novel insights into the molecular and cellular determinants of GB radioresistance and thus provide the basis for developing novel strategies for their radiosensitization. PUBLIC HEALTH RELEVANCE: Improving the efficacy of radiation as a treatment for glioblastoma (GB) will require a thorough understanding of the molecules and processes that contribute to their radioresistance, which necessitates taking into account the impact of the microenvironment. Towards this end, the proposed studies will delineate the fundamental determinants of GB radioresponse using orthotopic xenograft models. It is anticipated that these studies will provide novel insight into GB radioresistance and thus provide the basis for developing novel strategies for their radiosensitization.

描述（由申请人提供）： 尽管放疗可显着延长胶质母细胞瘤 (GB) 患者的生存期，但绝大多数患者会在诊断后 1-2 年内死于疾病。 该提案的总体目标是描述有助于 GB 辐射抗性的分子和过程。 传统上，人类 GB 放射反应的实验室研究主要集中在单层培养物和/或腿部肿瘤异种移植物中生长的肿瘤细胞系，本质上忽略了正常大脑环境的影响。 然而，我们的初步数据表明，已建立的 GB 细胞系的脑内生长改变了其基础和辐射诱导的基因表达谱。 该提议的首要前提是大脑微环境对 GB 放射反应具有决定性影响；因此，要了解 GB 辐射抗性的调节机制，有必要考虑其独特的原位环境。 为此，拟议的研究将重点关注从 CD133+ GB 肿瘤起始细胞 (TIC) 生长的脑内异种移植物。 与已建立的细胞系相比，从 TIC 生长的脑内异种移植物复制了原代 GB 的基因型/表型和体内生长模式；这样的异种移植物也可能​​最好地模拟大脑微环境对 GB 放射反应的影响。 拟议的研究将涉及 3 个目标。 第一个目标将确定原位生长对 GB TIC 的基础和辐射诱导基因表达谱的影响。 这些研究将涉及对体外和体内生长的腿部肿瘤和脑内异种移植物的 GB TIC 进行基于微阵列的转录组和基因翻译分析。 这些全基因组询问将检验原位环境独特地影响 GB TIC 基因表达的假设。 沿着这些思路，需要测试的另一个假设是 GB TIC 的放射反应包括在脑内条件下独特表达或诱导的蛋白质。 第二个目标将确定 TIC 脑内异种移植物内细胞的放射反应是否因拓扑和/或表型而异。 这些研究将检验以下假设：原位生长产生的肿瘤内异质性导致亚群具有不同程度的放射敏感性。 最后，第三个目标是检验以下假设：原位环境中存在独特的 GB 放射增敏目标。 研究将初步确定单次和分段放射方案控制 TIC 脑内异种移植物生长的能力。 然后将测试目标 1 和 2 建议的目标策略增强辐射诱导生长控制的能力。 预计这些研究将对 GB 放射抗性的分子和细胞决定因素产生新的见解，从而为开发新的放射增敏策略奠定基础。 公共卫生相关性： 提高放射治疗胶质母细胞瘤（GB）的疗效需要彻底了解导致其放射抗性的分子和过程，这需要考虑微环境的影响。 为此，拟议的研究将使用原位异种移植模型描述 GB 放射反应的基本决定因素。 预计这些研究将为 GB 放射抗性提供新的见解，从而为开发新的放射增敏策略奠定基础。