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（由适用提供）：胶质母细胞瘤（GBM）患者的管理仍然受到挑战。在肿瘤切除和标准化学放疗后，在复发性疾病的情况下，预后的中位生存期在不到一年的中位生存期很差。由于GBM通常以血管内皮生长因子（VEGF）介导的显着血管生成的特征，因此已经产生了靶向VEGF的重大兴趣。尽管已承诺并越来越多地在该患者人群中使用抗血管生成剂，例如贝伐单抗（靶向VEGF信号传导），但由于其对肿瘤脉管系统的独特影响，对这类药物的X光摄影反应的评估很困难。具体而言，可以通过标准处理后磁共振成像（MRI）看到的对比度增强，这不一定与施用VEGF靶向剂后可行肿瘤的减少相对应，VEGF靶向剂（一种称为“伪反应”）的伪响应。此外，并非所有患者都表现出抗血管生成疗法的临床益处，为什么在该患者人群中开发新颖且可靠的治疗反应成像生物标志物会解决主要的未满足需求并改善患者的管理。基于放射疗法肿瘤学组与美国放射学学院（RTOG 0825/ACRIN6677）合作进行的NIH资助的前瞻性临床试验，我们有强有力的证据表明，质子磁共振光谱谱谱图（1H MRSI）可以在GBM患者中与早期的肿瘤复发相关。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，该特征被认为独立于与肿瘤相关的血管生成和血管性状态。具体而言，MRS测量胆碱（CHO），胆碱（CHO）是一种加速膜合成的标记，发生在迅速分裂的癌细胞和N-乙酰天冬氨酸（NAA）中，这是神经元完整性的标志物，在肿瘤进展中受到损害。最近的研究表明，抗血管生成治疗后8周内NAA/CHO的变化可预测六个月的无进展生存期和整体存活率。基于这些研究，我们假设贝伐单抗治疗后NAA/CHO比率的显着下降可预测早期治疗失败。为了巩固这些发现，我们建议验证在两个队列中1H MRSI的应用：1）在接受贝伐单抗单药治疗的患者中，以及2）在接受基于贝伐单抗的化学疗法治疗的患者中。 3T MRI和MRSI将在抗VEGF治疗的倡议前以及治疗过程中的预定时间点进行。在接受抗血管生成疗法治疗的神经胶质瘤患者中，将MRS作为一种强大的成像生物标志物的强大成像生物标志物将为选择患者提供更好的疗法，节省成本并总体上改善患者管理的有效工具。