Prediction of Chemoradiation response in Glioblastoma to individualize Therapy

预测胶质母细胞瘤的放化疗反应以进行个体化治疗

• 批准号: 7450205
• 负责人: KENNETH D ALDAPE
• 金额: $ 27.27万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7450205
• 关键词: Adult; Angiogenesis Inhibitors; Area; BAY 54-9085; Biological Assay; Biological Markers; Brain Neoplasms; Candidate Disease Gene; Caring; Clinic; Clinical; Clinical Trials; Compatible; Complement; Data; Data Set; Databases; Diagnosis; Ensure; Extracellular Matrix; Formalin; Future; Gene Expression; Genes; Glioblastoma; Histopathology; Immunohistochemistry; MGMT gene; Medicine; Mesenchymal; Mesenchymal Differentiation; Meta-Analysis; Methylation; Microarray Analysis; Mining; Mitogen-Activated Protein Kinases; Molecular; Molecular Profiling; Newly Diagnosed; Outcome; Pathway interactions; Patients; Pattern; Phase; Phase III Clinical Trials; Phenotype; Phosphorylation; Progression-Free Survivals; Protein Overexpression; Radiation; Radiation Therapy Oncology Group; Radiation therapy; Randomized; Recurrence; Refractory; Resistance; Sampling; Signal Transduction; Staging; Standards of Weights and Measures; Statistical Models; Survival Rate; Techniques; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Treatment Protocols; University of Texas M D Anderson Cancer Center; Validation; angiogenesis; base; bevacizumab; chemotherapy; cohort; college; design; improved; inclusion criteria; inhibitor/antagonist; insight; next generation; novel; novel therapeutics; outcome forecast; promoter; prospective; research clinical testing; response; temozolomide; trial comparing; tumor

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.

胶质母细胞瘤（GBM）是成年人中最常见的原发性脑肿瘤，高度致命。最近的一个阶段 HI临床试验表明，仅放射线比替莫唑胺 - 化学化学（TMZ-CR）有好处。 尽管这些结果改变了新诊断的GBM患者的护理标准，但很明显 只有一部分患者从这种治疗中获得了显着的好处，总体两年生存 TMZ-CR治疗的患者仅26％。由于GBM的诊断和治疗决策目前是基于的 仅在组织病理学上，需要：1）为前瞻性地发展敏感和特定的标记 区分那些将对标准TMZ-CR作为初始治疗的患者与不会 回应; 2）确定定义抗性肿瘤设计的重要分子改变 对于不会单独从TMZ-CR中受益的患者的合理试验。我们已经开采了独立的微阵列 数据集识别一个初始的多标记面板，该图案可稳健地预测GBM中的结果。我们发现一个 由间充质/血管生成基因过表达定义的分子亚型，可预测不良 结果。在AIM 1中，将使用TMZ-CR处理的2组独立的肿瘤样品来完善该面板 德克萨斯大学M. D.安德森癌症中心（UTMDACC）和梅奥诊所的患者 医学院。我们将包括一组较大（-400）的基因，以确保最佳基因面板可以 可以鉴定出预测无进展生存的。我们将结合其他相关标记， 包括MGMT和AKT信号中间体。 AIM 2将严格测试并验证此多标记 使用来自大型III期临床试验的患者样品的面板。新开放的RTOG 05-25试验， 提交的要求提供了一个前所未有的机会来研究大型（n = 834）队列 使用现代分子技术统一治疗的GBM患者来确定一套确定的一组 预测标记。 AIM 3将集中于针对复发GBM的新型代理的响应标记 TMZ-CR失败的患者。预计大多数患者的肿瘤将显示 间充质/血管生成表型，因此我们将确定针对该的潜在药物 GBM中的表型。该项目的结果将为以后的试验奠定基础，在该试验中，新诊断 GBM患者将接受预测性测试，并根据分子进行个性化治疗 肿瘤的剖面，以最大程度地提高利益的机会。