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: 7991802
• 负责人: Philip Tofilon
• 金额: $ 31.19万
• 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 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7991802
• 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; 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）： 放疗显着延长了胶质母细胞瘤（GB）患者的存活率，而绝大多数在诊断后的1 - 2年内屈服于疾病。 该提案的总体目标是描述有助于GB放射线的分子和过程。 传统上，人类GB辐射响应的实验室研究主要集中在单层培养物和/或作为腿部肿瘤异种移植物中生长的肿瘤细胞系，本质上忽略了正常脑环境的影响。 但是，我们的初始数据表明，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。 该提议的主要前提是大脑微环境对GB辐射响应有决定性的影响。因此，要了解介导GB辐射势的机制，有必要考虑其在原地情况下的独特性。 为此，拟议的研究将重点放在CD133+ GB肿瘤启动细胞（TICS）中生长的脑异种移植物（TICS）。 与已建立的细胞系相反，源自抽动的脑内异种移植物复制基因型/表型和原代GBS的体内生长模式。然后，这种异种移植物也很可能可以最好地模拟脑微环境对GB辐射响应的后果。 拟议的研究将涉及3个目标。 第一个目标将定义原位生长对GB TICS基础和辐射诱导的基因表达谱的影响。 这些研究将涉及基于微阵列的转录组和GB TIC的基因翻译分析，并作为腿部肿瘤和脑内异种移植物在体外和体内生长。 这些全基因组的询问将检验以下假设：原位环境独特影响GB TIC基因表达。 沿着这些线路，要测试的另一个假设是GB TICS的辐射响应包括在脑内条件下以唯一表达或诱导的蛋白质。 第二个目标将确定脑内异种移植物中细胞的辐射响应是否根据拓扑和/或表型有所不同。 这些研究将检验以下假设：原位生长产生的肿瘤内异质性会导致射线敏感性不同的亚群。 最后，第三个目的是检验以下假设：原位环境特有的GB放射敏化目标。 研究最初将定义单个和分级辐射方案控制脑内异种移植的生长的能力。 然后，将对目标1和2提出的目标策略进行测试，以增强辐射引起的生长控制的能力。 可以预料，这些研究将产生对GB辐射抗性的分子和细胞决定因素的新见解，从而为开发新型策略的放射敏化提供了基础。 公共卫生相关性： 提高辐射作为胶质母细胞瘤（GB）的疗效将需要对有助于其放射线的分子和过程进行透彻的了解，这需要考虑到微环境的影响。 为此，提出的研究将使用原位异种移植模型描述GB辐射响应的基本决定因素。 可以预料，这些研究将为GB辐射抗性提供新的见解，从而为开发新型策略的放射敏化提供了基础。

项目成果

The DNA-PK Inhibitor VX-984 Enhances the Radiosensitivity of Glioblastoma Cells Grown In Vitro and as Orthotopic Xenografts.

• DOI: 10.1158/1535-7163.mct-17-1267
• 发表时间: 2018-06
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Timme CR;Rath BH;O'Neill JW;Camphausen K;Tofilon PJ
• 通讯作者: Tofilon PJ

Physiologic oxygen concentration enhances the stem-like properties of CD133+ human glioblastoma cells in vitro.

• DOI: 10.1158/1541-7786.mcr-08-0360
• 发表时间: 2009-04
• 期刊: Molecular cancer research : MCR
• 作者: McCord AM;Jamal M;Shankavaram UT;Lang FF;Camphausen K;Tofilon PJ
• 通讯作者: Tofilon PJ

CD133+ glioblastoma stem-like cells are radiosensitive with a defective DNA damage response compared with established cell lines.

• DOI: 10.1158/1078-0432.ccr-09-0263
• 发表时间: 2009-08-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: McCord AM;Jamal M;Williams ES;Camphausen K;Tofilon PJ
• 通讯作者: Tofilon PJ