Contextual Glioblastoma Screening For Efficacious Radiation Sensitizers

有效放射增敏剂的胶质母细胞瘤筛查

基本信息

批准号：
8769836
负责人：
Mary Helen Barcellos-Hoff
金额：
$ 25.43万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8769836
关键词：
Accounting Acute Address Adjuvant Radiotherapy Biological Biological Assay Brain Brain Neoplasms Cell Communication Cell Culture Techniques Cell Survival Cells Clinical Trials DNA Double Strand Break Diagnosis Disease Dose Excision Glioblastoma Heterogeneity Human In Situ In Vitro Knowledge Lead Link Malignant Neoplasms Measures Mediating Mesenchymal Modeling Molecular Molecular Profiling Newly Diagnosed Operative Surgical Procedures Patients Pharmaceutical Preparations Preclinical Drug Evaluation Prevalence Primary Brain Neoplasms Property Radiation Radiation Tolerance Radiation therapy Radiation-Sensitizing Agents Radiobiology Radioresistance Radiosensitization Regulation Relative (related person)Research Research Personnel Resistance Series Signal Transduction Specimen Stem cells Testing Tissues Work Xenograft procedure base cancer stem cell cancer therapy chemotherapy drug efficacy drug testing in vivo inhibitor/antagonist neoplastic cell neutralizing antibody novel novel strategies outcome forecast preclinical study prevent public health relevance radiation effect radiation resistance relating to nervous system repaired research study response screening small molecule standard of care stem cell biology temozolomide tumor tumor initiation tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): The prognosis for patients with glioblastoma multiforme (GBM) remains extremely poor despite decades of research. The current standard of care for newly diagnosed glioblastoma is surgical resection to the extent feasible, followed by adjuvant radiotherapy and temozolomide chemotherapy. GBM tumor cells in situ are considered to be radioresistant, which is classically thought to be a cell-intrinsic property. However, recent studies point to the contribution of two non-classical mechanisms that contribute to radiation resistance in GBM: glioblastoma stem cells (GSCs) and the tumor microenvironment (TME). While GSCs employ defined molecular mechanisms that lead to radioresistance, these mechanisms are dramatically potentiated in vivo, suggesting a strong TME influence. Given that non-classical radioresistance in GBM is modulated by the TME, it follows that testing of radiosensitizing agents cannot be performed in cell culture. Instead, novel testing platforms are required that both provide appropriate biological context that takes into account the TME, as well as allow for rapid drug testing. Such testing is further complicated by intertumoral heterogeneity in GBM. The identification of four major molecular GBM subtypes that have different prognoses motivates concerns that such heterogeneity may confound drug testing if specific radiosensitizing agents are efficacious in one subtype but not others. Here we propose to implement a novel approach to screen contextual GBM response to radiosensitizers using organotypic culture of human GBM operative specimens to evaluate the molecular and cellular response to radiation in situ. Based on our preclinical studies and the knowledge of current GBM clinical trials, we propose to evaluate TGF¿ inhibition as a means to increase GBM radiosensitivity to validate this testing platform. The proposed experiments are based on the hypothesis that response to radiation is enhanced by inhibition of TGF¿ in the form of decreased recognition and repair of radiation-induced double-stranded DNA breaks (DSBs). We predict that inhibition of TGF¿ signaling will prevent the observed radiation-induced increase in the prevalence of GSCs in organotypic cultures, as measured by functional clonogenic assays and tumor initiation potential. Importantly, we will evaluate the relative efficacy of TGF¿ inhibitors as radiosensitizers in human GBM specimens representing all molecular subtypes previously described. We posit that this approach, which preserves TME and GSC contributions to GBM radiobiology in an ex vivo setting, will allow for efficient drug screening by incorporating both cellular and functional readouts for drug efficacy, as well as by examining drug effects in distinct molecular subtypes of GBM. Importantly, we envision this approach becoming a paradigm for discovery of radiosensitizing agents that can be applied to other brain tumors.

描述（由适用提供）：多形胶质母细胞瘤（GBM）患者的预后仍然非常糟糕。当前针对新诊断的胶质母细胞瘤的护理标准是手术切除术，随后是可行的，然后是调整放射疗法和替莫唑胺化学疗法。 GBM肿瘤细胞原位被认为是放射性的，从经典上讲，这是一种细胞内部特性。但是，最近研究表明，两种非经典机制的贡献，这些机制有助于GBM中的辐射耐药性：胶质母细胞瘤干细胞（GSC）和肿瘤微环境（TME）。尽管GSC采用了导致辐射势的定义的分子机制，但这些机制在体内动态潜在，表明TME的影响很强。鉴于GBM中的非古典辐射抗性是由TME调节的，因此可以在细胞培养中进行放射敏化剂的测试。取而代之的是，需要提供新颖的测试平台，以提供适当的生物学环境，以考虑到TME，并允许快速的药物测试。 GBM中的肿瘤异质性进一步使这种测试更加复杂。具有不同预后的四种主要分子GBM亚型的鉴定激发了人们担心这种异质性可能会混淆药物测试，如果特定的放射敏化剂在一种亚型中有效而不是其他亚型，而不是其他。在这里，我们建议使用人类GBM操作规范的有机培养物来筛选上下文GBM对放射增感器的响应，以评估分子和细胞对辐射原位的反应。根据我们的临床前研究和当前GBM临床试验的了解，我们建议评估TGF抑制作用，以此作为增加GBM放射敏感性以验证该测试平台的一种手段。所提出的实验是基于以下假设：对辐射的反应通过抑制TGF的反应以减少识别和修复辐射诱导的双链DNA断裂（DSB）的形式。我们预测，通过功能性下降测定和肿瘤的启动潜力来衡量，TGF¿信号传导的抑制作用将阻止观察到的有机培养物中GSC患病率的增加。重要的是，我们将评估TGF¿抑制剂的相对效率，作为代表先前描述的所有分子亚型的人类GBM标本中的放射增敏剂。我们指出，这种方法可以在离体环境中保留TME和GSC对GBM放射生物学的贡献，它将允许通过同时将细胞和功能读数纳入药物效率，以及通过在GBM的不同分子亚型中检查药物效应。重要的是，我们设想这种方法成为发现可以应用于其他脑肿瘤的放射性敏感剂的范式。