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（由申请人提供）：尽管经过数十年的研究，多形性胶质母细胞瘤（GBM）患者的预后仍然极差，目前新诊断的胶质母细胞瘤的护理标准是在可行的范围内进行手术切除，然后进行辅助放疗和替莫唑胺化疗。原位 GBM 肿瘤细胞被认为具有放射抗性，这通常被认为是细胞固有的特性。研究指出，两种非经典机制有助于 GBM 的辐射抵抗：胶质母细胞瘤干细胞 (GSC) 和肿瘤微环境 (TME)。虽然 GSC 采用导致辐射抵抗的明确分子机制，但这些机制在 GBM 中显着增强。鉴于 GBM 中的非经典放射抗性是由 TME 调节的，因此放射增敏剂的测试不能在细胞培养物中进行。相反，需要新的测试平台来提供考虑 TME 的适当生物学环境，并允许快速药物测试，这种测试因 GBM 的肿瘤间异质性而变得更加复杂。 GBM 的四种主要分子亚型的鉴定。不同的预后引发了人们的担忧，即如果特定的放射增敏剂对一种亚型有效但对其他亚型无效，这种异质性可能会混淆药物测试。在此，我们建议实施一种新方法来筛选 GBM 的背景反应。基于我们的临床前研究和当前 GBM 临床试验的知识，我们建议使用人类 GBM 手术标本的器官培养来评估对放射的分子和细胞反应。抑制作为增加 GBM 放射敏感性的一种手段来验证该测试平台所提出的实验基于抑制 TGF 增强对辐射的反应的假设。我们预测 TGF 的抑制会导致辐射诱导的双链 DNA 断裂 (DSB) 的识别和修复减少。信号传导将观察到辐射诱导的器官型培养物中 GSC 患病率的增加，通过功能性克隆形成测定和肿瘤起始潜力进行测量，重要的是，我们将阻止 TGF 的相对功效。我们认为，这种方法在离体环境中保留了 TME 和 GSC 对 GBM 放射生物学的贡献，将允许通过以下方法进行有效的药物筛选。结合细胞和功能读数来了解药物疗效，并通过检查药物对 GBM 不同分子亚型的影响，我们预计这种方法将成为发现可应用于其他脑肿瘤的放射增敏剂的范例。