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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）：尽管几十年的研究，多形性胶质母细胞瘤（GBM）患者的预后仍然非常差。对于新诊断的胶质母细胞瘤，目前的治疗标准是手术切除，然后辅以放疗和替莫唑胺化疗。原位GBM肿瘤细胞被认为是耐辐射的，这通常被认为是细胞固有的特性。然而,最近