Prediction of Chemoradiation response in Glioblastoma to individualize Therapy

胶质母细胞瘤（GBM）是成人中最常见的原发性脑肿瘤，并且是高度致命的。最近的一个阶段 HI临床试验证明替莫唑胺-放化疗（TMZ-CR）优于单纯放疗。 虽然这些结果改变了新诊断GBM患者的护理标准，但很明显， 只有一小部分患者从这种治疗中获得了显著的益处， TMZ-CR治疗的患者仅占26%。由于GBM的诊断和治疗决策目前基于 仅就组织病理学而言，需要：1）开发敏感和特异的标记物， 将标准TMZ-CR作为初始治疗应答的患者与不应答的患者区分开来 反应;和2）确定定义耐药肿瘤的重要分子改变以设计 对不能从TMZ-CR单药治疗中获益的患者进行合理试验。我们挖掘了独立的微阵列 数据集，以确定稳健预测GBM结果的初始多标记物组。我们发现一个 分子亚型，定义为间充质/血管生成基因的过度表达， 结果。在目标1中，将使用来自TMZ-CR治疗组的2组独立肿瘤样本完善该样本组 德克萨斯大学M. D.安德森癌症中心（UTMDACC）和马约诊所 医学院。我们将包括一个更大的（-400）基因集，以确保最佳的基因面板可以 可以预测无进展生存期。我们会加入其他相关标记， 包括MGMT和Akt信号传导中间体。AIM 2将严格测试和验证这种多标记 使用来自大型III期临床试验的患者样本的面板。新开放的RTOG 05-25试验， 组织提交要求，为研究大型（n=834）队列提供了前所未有的机会 统一治疗的GBM患者使用现代分子技术，以确定一组明确的 预测标记。目标3将集中于新药物对复发性GBM的反应标志物 TMZ-CR失败的患者。预计这些患者中的大多数肿瘤将显示出 间充质/血管生成表型，因此我们将鉴定靶向 GBM中的表型。该项目的结果将为未来的试验奠定基础，其中新诊断的 GBM患者将接受预测性测试，治疗将根据分子水平进行个体化。 以最大化获益的机会。

Glioblastoma (GBM) is the most common primary brain tumor in adults and is highly lethal. A recent phase HI clinical trial demonstrated a benefit for temozolomide-chemoradiation (TMZ-CR) over radiation alone. While these results have changed the standard of care for newly diagnosed GBM patients, it is clear that only a fraction of patients derive significant benefit from this treatment, with overall two-year survival in the TMZ-CR treated patients only 26%. Since diagnosis and treatment decisions in GBM are currently based on histopathology alone, there is a need to: 1) develop sensitive and specific markers to prospectively distinguish those patients who will respond to standard TMZ-CR as initial treatment from those who will not respond; and 2) determine important molecular alterations that define the resistant tumors to design rational trials for patients who will not benefit from TMZ-CR alone. We have mined independent microarray datasets to identify an initial multimarker panel that robustly predicts outcome in GBM. We find that a molecular subtype, defined by overexpression of mesenchymal/angiogenic genes, is predictive of poor outcome. In Aim 1, will refine this panel using 2 independent sets of tumor samples from TMZ-CR treated patients at The University of Texas M. D. Anderson Cancer Center (UTMDACC) and the Mayo Clinic College of Medicine. We will include a larger (-400) set of genes to ensure that an optimal gene panel can be identified that predicts progression-free survival. We will incorporate additional relevant markers, including MGMT and Akt signaling intermediates. Aim 2 will rigorously test and validate this multimarker panel using patient samples from a large phase III clinical trial. The newly opened RTOG 05-25 trial, with a requirement of tissue submission, provides an unprecedented opportunity to study a large (n=834) cohort of uniformily-treated GBM patients using modern molecular techniques to identify a definitive set of predictive markers. Aim 3 will focus on markers of response from novel agents targeted to recurrent GBM patients who have failed TMZ-CR. It is expected that tumors from most of these patients will display the mesenchymal/angiogenic phenotype, and we will therefore identify potential agents which target that phenotype in GBM. The results of this project will set the stage for future trials, in which newly diagnosed GBM patients will undergo a predictive test, and treatment will be individualized according to the molecular profile of the tumor to maximize the chances of benefit.