Prediction of Chemoradiation response in Glioblastoma to individualize Therapy

胶质母细胞瘤(GBM)是成人最常见的原发脑肿瘤，具有很高的致命性。最近的一个阶段 临床试验证明替莫唑胺联合化疗(TMZ-CR)优于单纯放疗。 虽然这些结果改变了新诊断的GBM患者的护理标准，但显然 只有一小部分患者从这种治疗中获得显著好处，总的两年存活率在 接受TMZ-CR治疗的患者仅占26%。由于GBM的诊断和治疗决策目前是基于 仅就组织病理学而言，有必要：1)开发敏感和特异的标记物来前瞻性地 区分那些对标准TMZ-CR作为初始治疗有反应的患者和那些不会有反应的患者 响应；以及2)确定定义要设计的耐药肿瘤的重要分子改变 对不会单独从TMZ-CR受益的患者进行合理的试验。我们已经挖掘出独立的基因芯片 数据集，以确定最初的多标记面板，有力地预测GBM的结果。我们发现一个 分子亚型，由间充质/血管生成基因的过度表达定义，是不良的预测因素 结果。在目标1中，将使用来自TMZ-CR治疗的两组独立的肿瘤样本来优化该小组 德克萨斯大学安德森癌症中心(UTMDACC)和梅奥诊所的患者 医学院。我们将包括更大的(-400)组基因，以确保最优的基因小组可以 被确认为预测无进展生存。我们将加入更多的相关标志， 包括MGMT和Akt信号中间体。目标2将严格测试和验证这个多标记 专家小组使用来自大型III期临床试验的患者样本。新开庭的RTOG 05-25审判， 组织提交的要求，为研究大规模(n=834)队列提供了前所未有的机会 使用现代分子技术对接受统一治疗的GBM患者进行研究 预测性标记。目标3将重点放在针对复发性GBM的新型药物的反应标记上 未通过TMZ-CR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，因此我们将确定以此为靶点的潜在药物 GBM的表型。该项目的结果将为未来的试验奠定基础，在这些试验中，新诊断的 GBM患者将接受预测性测试，并根据分子水平进行个体化治疗 以最大限度地增加受益机会。

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.