Predictive Imaging Biomarkers for GBM Therapeutic Response and Recurrence

原发性GBM，占人类GBM的90%以上，在没有先前临床表现的情况下迅速或从头发展。 疾病大规模的基因组分析极大地促进了胶质瘤的定义 景观和数据集（TCGA）已经使得GBM能够基于它们的基因组划分为子类， 转录组学和信号转导模式。可悲的是，尽管这些见解的遗传学的 尽管神经外科、放射治疗和化学治疗的进步， 显著胶质母细胞瘤（GBM）治疗的当前范例基于以下概念： 接受由替莫唑胺和电离辐射（TMZ/IR）组成的标准治疗， 如果他们能从一线治疗中受益，完成治疗后，延迟一个月 (or更多），以评估结果。发现无反应的患者被分配到二线治疗 GBM患者的护理在当前时代是次优的，其中用于治疗GBM的技术在当今时代是次优的。 全基因组测序是一个现实，因此能够使用基于靶向药物的个性化药物 每个病人的基因改变是可能的。该项目将建立基于体素的 用于检测早期治疗反应和肿瘤复发的定量MRI衍生指标 TMZ/IR治疗和分子靶向治疗给药期间。具体目标1将进行 参数响应图（PRM）作为早期乳腺癌基于体素的成像生物标志物的多中心验证 新诊断的胶质母细胞瘤的标准治疗反应。在移植时收获的肿瘤 最初的手术切除将由项目1进行基因分析，以进行反应性分层。具体 目标2将评价II期（MCC-15412/ABTC-0703）和I期的PRM早期反应成像指标 （RTOG-0825/ACR 1 N-6686）分子靶向药物在新诊断患者中的临床试验 恶性神经胶质瘤具体目标3将开发和评估一种新的PRM方法， 通过目前可用的方法，在检测之前对早期GBM进展进行客观检测和空间描述 常规MRI标准。总体而言，本项目旨在推进临床应用， 新的基于MRI的生物标志物度量作为患者肿瘤状态的定量和预测替代物的效用。 这些方法将提供成像如何可以集成到临床的显着改善 试验以及改善GBM患者的临床管理和护理。总体而言，这一努力是预期的， 以改善这一患者群体的预后。

Primary GBM, accounting for over 90% of human GBMs, develops rapidly or de novo with no prior clinical disease. Large-scale genomic analyses have contributed greatly to the definition of the overall glioma landscape and datasets (TCGA) have enabled the division of GBMs into subclasses based on their genomic, transcriptomic, and signal transduction patterns. Sadly, despite these insights into the genetics of the disease and advances in neurosurgery, radiation and chemotherapy, its dismal prognosis has not changed significantly. The current paradigm for glioblastoma (GBM) therapy is based on the concept that each patient is treated with the standard of care consisting of temozolomide and ionizing radiation (TMZ/IR) with no upfront knowledge if they will benefit from first-line therapy. Following completion of treatment, a month delay (or more) is needed to assess outcome. Patients found nonresponsive are assigned to a second-line treatment and so on. Care of GBM patients is sub-optimal in the current era wherein the technology for whole genome sequencing is a reality and thus enabling personalized medicine using targeted agents based on genetic alterations of each patient is possible. This Project will establish the accuracy of voxel-based quantitative MRI-derived metrics for detection of early treatment response and tumor recurrence during TMZ/IR treatment and during administration of molecularly targeted therapies. Specific Aim 1 will conduct a multi-center validation of the parametric response map (PRM) as a voxel-based imaging biomarker of early response in standard of care treatment of newly diagnosed glioblastoma. Tumors harvested at the time of initial surgical excision will be genetically profiled by Project 1 for stratification with responsiveness. Specific Aim 2 will evaluate PRM early response imaging metrics in Phase II (MCC-15412/ABTC-0703) and Phase 1 (RTOG-0825/ACR1N-6686) clinical trials of molecularly targeted agents in patients with newly diagnosed malignant glioma. Specific Aim 3 will develop and evaluate a novel PRM approach for automated and objective detection and spatial depiction of early GBM progression prior to detection by currently available conventional MRI-based criteria. Overall, this Project is designed to advance the clinical application and utility of novel MRI-based biomarker metrics as quantitative and predictive surrogates of patient tumor status. These approaches will provide for significant improvements in how imaging can be integrated into clinical trials as well as in improving clinical management and care of GBM patients. Overall, this effort is anticipated to lead to improved outcome for this patient population.