Predictive Imaging Biomarkers for GBM Therapeutic Response and Recurrence

原发基底膜占人类基底膜的90%以上，发展迅速或从头开始，无临床先例。 疾病。大规模的基因组分析对整个胶质瘤的定义做出了很大贡献。 景观和数据集(TCGA)使基于其基因组将GBM划分为亚类成为可能， 转录和信号转导模式。可悲的是，尽管有这些对人类基因的洞察 疾病和神经外科、放射和化疗的进展，其令人沮丧的预后没有改变 意义重大。目前的胶质母细胞瘤(GBM)治疗模式是基于这样一个概念：每个患者 采用由替莫唑胺和电离辐射(TMZ/IR)组成的护理标准进行治疗，不含NO 如果他们将从一线治疗中受益，他们将预先了解。治疗结束后，延迟一个月 (或更多)来评估结果。被发现无反应的患者被分配到二线 治疗等等。在当今时代，对GBM患者的护理是次优的，因为 全基因组测序成为现实，从而使基于靶向试剂的个性化药物成为可能 每个患者的基因改变是可能的。该项目将建立基于体素的精度 MRI衍生的定量指标用于检测早期治疗反应和肿瘤复发 TMZ/IR治疗和分子靶向治疗期间。特定目标1将进行一次 参数反应图(PRM)作为早期基于体素的成像生物标记物的多中心验证 新诊断的胶质母细胞瘤标准治疗中的反应。在此期间采集到的肿瘤 最初的手术切除将由项目1进行遗传学分析，以进行分层和反应。特定的 AIM 2将评估第二阶段(MCC-15412/ABTC0703)和第一阶段的PRM早期反应成像指标 (RTOG-0825/ACR1N-6686)分子靶向药物治疗初诊患者的临床试验 恶性胶质瘤。具体目标3将开发和评估一种新的PRM方法，用于自动化和 目前可用的方法在检测前对早期基底膜进展的客观检测和空间描述 常规的基于MRI的标准。总体而言，该项目旨在促进临床应用和 新的基于核磁共振成像的生物标记物指标作为患者肿瘤状态的定量和预测替代指标的应用。 这些方法将在如何将成像整合到临床上提供显著的改进 试验以及改善GBM患者的临床管理和护理。总体而言，这一努力是可以预期的 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.