Evaluation of impact of anti-VEGF drugs on concomitant chemotherapy in GBM

抗VEGF药物对GBM联合化疗的影响评价

• 批准号: 8699478
• 负责人: Elizabeth Gerstner
• 金额: $ 17.93万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8699478
• 关键词: Affect; Area; Biological Markers; Blood; Blood Vessels; Blood Volume; Blood flow; Brain; Brain Neoplasms; CXCL12 gene; Caliber; Cephalic; Cerebrovascular Circulation; Core-Binding Factor; Cytotoxic Chemotherapy; Cytotoxic agent; Data; Drug usage; Equilibrium; Glioblastoma; Goals; Health; Heterogeneity; Hypoxia; Impact evaluation; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Neoplasms; Maps; Measures; Metabolic; Newly Diagnosed; Oxygen; PGF gene; Patients; Penetration; Perfusion; Permeability; Pharmaceutical Preparations; Pharmacodynamics; Physiology; Positron-Emission Tomography; Predisposition; Progression-Free Survivals; Radiolabeled; Recurrence; Resistance; Techniques; Therapeutic; Treatment Protocols; Tumor Biology; Tumor Immunity; Tumor Oxygenation; United States; United States Food and Drug Administration; Vascular Endothelial Growth Factors; Vascular Permeabilities; bevacizumab; chemoradiation; chemotherapy; cranium; cytotoxic; improved; novel; patient population; phase 3 study; radiotracer; response; temozolomide; therapeutic target; tool; tumor

DESCRIPTION (provided by applicant): Glioblastomas (GBMs) are malignant, invasive, incurable brain tumors that are poorly responsive to chemotherapy. The abnormal tumor vasculature that is a pathological hallmark of GBM is a potential mechanism of tumor resistance to cytotoxic therapies and may represent an important therapeutic target. Biologic agents such as bevacizumab, which target vascular endothelial growth factor (VEGF) are being studied in GBM and have resulted in improved progression-free survival in patients. Bevacizumab was approved by the Food and Drug Administration in 2009 as monotherapy for recurrent GBM and is now widely used in the United States in this patient population. It is unclear why patients respond to anti-VEGF treatment and what is the optimal way to incorporate these drugs into treatment regimens. The strong anti-permeability effect of anti-VEGF agents decreases the mass effect of tumors within the fixed cranial vault but may also decrease the penetration of cytotoxic chemotherapies into the tumor. However, this decrease in permeability may be offset by improvement in tumor blood flow. Improved blood flow to the tumor may actually improved delivery of cytotoxic chemotherapies to areas of the tumor that previously had not been well perfused and, thus, exposed to cytotoxic drugs. The goal of this proposal is to understand how anti-VEGF agents modulate the delivery of temozolomide, a standard chemotherapy agent used to treat GBM. We will use simultaneously acquired MRI and PET to measure vascular physiology and delivery of temozolomide in patients with recurrent GBM treated with bevacizumab. Fifteen patients will undergo MRI and FMISO PET to measure vascular changes and change in tumor oxygenation status in response to bevacizumab. An additional 15 patients will undergo MRI and PET with radiolabeled temozolomide to measure delivery and penetration of temozolomide into the tumor before and during treatment with bevacizumab.

描述（由申请人提供）：胶质母细胞瘤（GBMs）是恶性的、侵袭性的、无法治愈的脑肿瘤，对化疗反应差。异常的肿瘤血管系统是GBM的病理标志，是肿瘤对细胞毒性治疗产生耐药性的潜在机制，可能是一个重要的治疗靶点。靶向血管内皮生长因子（VEGF）的生物制剂如贝伐单抗（bevacizumab）正在GBM中进行研究，并已改善患者的无进展生存期。贝伐单抗于2009年获得美国食品和药物管理局批准，作为复发性GBM的单药治疗，目前在美国广泛用于该患者群体。目前尚不清楚为什么患者对抗vegf治疗有反应，以及将这些药物纳入治疗方案的最佳方法是什么。抗vegf药物的强抗渗透作用降低了固定颅穹内肿瘤的质量效应，但也可能降低细胞毒性化疗对肿瘤的渗透。然而，这种通透性的降低可能被肿瘤血流的改善所抵消。改善肿瘤的血流量实际上可能会改善细胞毒性化疗对肿瘤区域的输送，这些区域以前没有很好地灌注，因此暴露于细胞毒性药物。该提案的目的是了解抗vegf药物如何调节替莫唑胺的递送，替莫唑胺是一种用于治疗GBM的标准化疗药物。我们将使用同时获得的MRI和PET来测量血管生理学和替莫唑胺在接受贝伐单抗治疗的复发性GBM患者中的传递。15名患者将接受MRI和FMISO PET检查，以测量血管变化和肿瘤氧合状态的变化对贝伐单抗的反应。另外15名患者将接受放射标记替莫唑胺的MRI和PET检查，以测量替莫唑胺在贝伐单抗治疗前和治疗期间进入肿瘤的输送和渗透情况。