Identifying Early Failure to Anti-angiogenic Therapy in Recurrent GBM

识别复发性 GBM 抗血管生成治疗的早期失败

• 批准号: 9332321
• 负责人: Eva-Maria Ratai
• 金额: $ 34.8万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-07 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9332321
• 关键词: Address; Aftercare; American College of Radiology Imaging Network; Angiogenesis Inhibitors; Blood - brain barrier anatomy; Blood Vessels; Characteristics; Choline; Clinical; Clinical Trials; Collaborations; Complement; Cytotoxic Chemotherapy; Cytotoxic agent; Data; Development; Diagnostic radiologic examination; Early treatment; Excision; Failure; Funding; Glioblastoma; Glioma; Goals; Imaging Device; Lomustine; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Malignant neoplasm of brain; Measures; Mediating; Medical; Metabolism; Methods; Monitor; N-acetylaspartate; Neurons; Operative Surgical Procedures; Outcome; Patient Care; Patients; Perfusion Weighted MRI; Progression-Free Survivals; Public Health; Quality of life; Radiation Therapy Oncology Group; Recurrence; Recurrent disease; Signal Transduction; Testing; Time; Treatment Failure; Tumor Biology; Tumor Markers; United States National Institutes of Health; Validation; Vascular Endothelial Growth Factors; alternative treatment; angiogenesis; base; bevacizumab; blood vessel development; cancer cell; cancer type; chemoradiation; chemotherapy; cohort; contrast enhanced; cost; cytotoxic; feeding; hemodynamics; imaging biomarker; imaging modality; improved; interest; magnetic resonance spectroscopic imaging; membrane synthesis; metabolic profile; neovascular; novel; outcome forecast; patient population; patient subsets; prospective; public health relevance; response; standard of care; targeted agent; temozolomide; tool; treatment response; tumor; tumor metabolism; tumor progression

 DESCRIPTION (provided by applicant): Management of patients with glioblastoma (GBM) remains challenging. Prognosis is quite poor with a median survival of less than one year in the setting of recurrent disease after tumor resection and standard chemoradiation. As GBM is typically characterized by marked angiogenesis mediated by vascular endothelial growth factor (VEGF), significant interest has been generated towards targeting VEGF. While anti-angiogenic agents such as bevacizumab (which is targeting VEGF signaling) has been promising and increasingly used in this patient population, assessment of radiographic response with this class of agents has been difficult due to their unique effects on the tumor vasculature. Specifically, diminished contrast enhancement as it can be seen with standard post-treatment magnetic resonance imaging (MRI) may not necessarily correspond to reduction in viable tumor after administration of VEGF-targeting agents, a phenomenon called "pseudo-response". Moreover, not all patients demonstrate clinical benefit from anti-angiogenic therapies, why the development of novel and reliable imaging biomarkers of treatment response in this patient population would address a major unmet need and improve patient management. Based on an NIH-funded prospective clinical trial performed by the Radiation Therapy Oncology Group in collaboration with American College of Radiology Imaging Network (RTOG 0825/ACRIN6677) we have strong evidence to suggest that proton magnetic resonance spectroscopic imaging (1H MRSI) can reliably identify early tumor recurrence in GBM patients. We speculate that the main advantage of using MRS is based on the ability to monitor cellular tumor metabolism, a feature considered independent of the state of tumor- related angiogenesis and vascularity. Specifically, MRS measures choline (Cho), a marker for accelerated membrane synthesis that occurs in rapidly dividing cancer cells and N-Acetylaspartate (NAA), a marker for neuronal integrity, which is compromised in tumor progression. Recent studies have shown that changes in NAA/Cho at 8 weeks post anti-angiogenic treatment were predictive of six-month progression-free survival and overall survival. Based on these studies, we hypothesize that a significant decline in the NAA/Cho ratio after bevacizumab treatment is predictive of early treatment failure. To consolidate these findings, we propose to validate the application of 1H MRSI in two cohorts: 1) in patients receiving bevacizumab monotherapy, and 2) in patients treated with bevacizumab-based chemotherapy. 3T MRI and MRSI will be performed before initiation of anti-VEGF therapy and at predetermined time points during treatment. Validation of MRS as a powerful imaging biomarker of treatment response in glioma patients treated with anti-angiogenic based therapies would add an effective tool to select patients to better therapies, save costs and overall improve patient management.

 描述（由申请人提供）：胶质母细胞瘤（GBM）患者的管理仍然具有挑战性。在肿瘤切除和标准化放疗后复发疾病的情况下，预后相当差，中位生存期不到一年。由于GBM的典型特征是由血管内皮生长因子（VEGF）介导的显著的血管生成，因此对靶向VEGF产生了显著的兴趣。虽然抗血管生成剂如贝伐单抗（靶向VEGF信号传导）已被看好并越来越多地用于该患者人群，但由于其对肿瘤血管系统的独特作用，难以评估此类药物的放射学反应。具体而言，如可以用标准治疗后磁共振成像（MRI）看到的对比度增强减弱可能不一定对应于施用VEGF靶向剂后存活肿瘤的减少，这是一种称为“假反应”的现象。此外，并非所有患者都表现出抗血管生成治疗的临床获益，因此在该患者人群中开发新型可靠的治疗反应成像生物标志物将解决主要未满足的需求并改善患者管理。 基于NIH资助的前瞻性临床试验，由放射治疗肿瘤学小组与美国放射学会成像网络（RTOG 0825/ACRIN 6677）合作进行，我们有强有力的证据表明，质子磁共振光谱成像（1H MRSI）可以可靠地识别GBM患者的早期肿瘤复发。我们推测，使用MRS的主要优点是基于监测细胞肿瘤代谢的能力，这一特征被认为与肿瘤相关的血管生成和血管分布的状态无关。具体而言，MRS测量胆碱（Cho），一种在快速分裂的癌细胞中发生的加速膜合成的标志物，以及N-乙酰天冬氨酸（NAA），一种在肿瘤进展中受损的神经元完整性的标志物。最近的研究表明，抗血管生成治疗后8周时NAA/Cho的变化可预测6个月的无进展生存期和总生存期。基于这些研究，我们假设贝伐单抗治疗后NAA/Cho比值的显著下降预示着早期治疗失败。 为了巩固这些发现，我们建议在两个队列中验证1H MRSI的应用：1）接受贝伐珠单抗单药治疗的患者，2）接受基于贝伐珠单抗的化疗的患者。将在开始抗VEGF治疗前和治疗期间的预定时间点进行3 T MRI和MRSI。MRS作为胶质瘤患者抗血管生成治疗反应的强大成像生物标志物的验证将增加一个有效的工具，以选择患者更好的治疗，节省成本和整体改善患者管理。