Predictive Markers of Glioblastoma Response to VEGF Trap

胶质母细胞瘤对 VEGF 陷阱反应的预测标志物

• 批准号: 7429709
• 负责人: JOHN F DE GROOT
• 金额: $ 29.26万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7429709
• 关键词: Angiogenic Factor; Animals; Basement membrane; Binding; Biological Markers; Biology; Blood; Blood Vessels; Brain Neoplasms; Cell Proliferation; Chimeric Proteins; Clinical; Clinical Pharmacology; Clinical Trials; Clinical Trials Design; Complex; Data; Development; Diffusion; Disease; Drug Kinetics; Endothelial Cells; Enrollment; Epidermal Growth Factor Receptor; Evaluation; Family; Fibroblast Growth Factor 2; Future; Glioblastoma; Glioma; Goals; Growth Factor; Human; Image; Immunohistochemistry; Institution; Invasive; Ligands; Link; MAP Kinase Gene; Magnetic Resonance Imaging; Maintenance; Maps; Measurement; Measures; Mediating; Methodology; Mitogens; Modeling; Molecular; Monitor; Mus; Neoplasms in Vascular Tissue; North American Brain Tumor Consortium; Numbers; Operative Surgical Procedures; Outcome; PTEN gene; Pathologic; Pathway interactions; Patients; Pattern; Permeability; Pharmacodynamics; Pharmacology; Phase; Phase II Clinical Trials; Phenotype; Placental Growth Factor; Plasma; Platelet-Derived Growth Factor; Pre-Clinical Model; Progression-Free Survivals; Protein Isoforms; Protein Overexpression; Radiation; Rate; Recurrence; Research; Resistance; Sampling; Signal Pathway; Stem cells; Time; Tissues; Tumor Biology; Tumor Escape; Tumor Tissue; Upper arm; Urine; VEGF Trap; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vascular Proliferation; Vascularization; Work; Xenograft Model; Xenograft procedure; angiogenesis; base; chemotherapy; density; extracellular; hypoxia inducible factor 1; improved; migration; outcome forecast; pharmacodynamic model; preclinical study; predictive modeling; receptor; resistance mechanism; response; temozolomide; trend; tumor; tumor growth

DESCRIPTION (provided by applicant): Glioblastoma is the most common type of primary brain tumor and carries a grave prognosis. Despite maximal therapy including surgery and combination radiation with chemotherapy median survival is 14 months with less than 5% of patients remaining alive at 5 years. New treatment approaches are needed to halt progression of this devastating disease. Endothelial proliferation is a pathologic hallmark of glioblastoma and studies have shown that the expression of pro-angiogenic factors such as vascular endothelial growth factor (VEGF) is one mechanism by which tumors induce the formation of new blood vessels. VEGF is a specific endothelial cell mitogen, permeability and survival factor, and is overexpressed in virtually all human tumors including glioblastoma. VEGF Trap is a recombinantly-produced fusion protein which scavenges free VEGF and placental growth factor (PlGF) removing important ligands for the VEGF family receptors. In preclinical studies, VEGF Trap significantly increased survival of mice bearing intracranial glioma xenografts. Anti-VEGF therapy is known to alter contrast enhancement patterns on MRI, but it is not known if this accurately reflects changes in tumor biology or will be predictive of long-term outcome. We are proposing to study biomarkers of response in patients with temozolomide-resistant glioblastoma enrolled in the North American Brain Tumor Consortium (NABTC) VEGF Trap phase II clinical trial. To assess the biologic activity of VEGF Trap and to develop predictive biomarkers of response, we will incorporate the measurement of multiple pharmacokinetic and pharmacodynamic parameters. Plasma and urine levels of free VEGF and PlGF and VEGF Trap pharmacology will be correlated with outcome as measured by 6-month progression free survival (PFS). Samples from patients who progress or do not respond will be evaluated for circulating growth factors mediating "tumor escape." Pre-treatment tumor tissue will be examined for molecular markers and vascularity and circulating endothelial cells will be measured as potential determinants of response. Biomarkers will be evaluated before treatment and at serial time points after initiation of therapy with the goal of determining the association between tumor-specific and circulating biomarkers of activity against endothelial cells and patient outcome. Based on dynamic contrast enhanced MRI changes, we will use statistical and pharmacodynamic modeling to incorporate these measures into a predictive model of response. These studies are critical to establish which biomarkers are useful in predicting response and monitoring treatment progress, as well as for forming a baseline for biomarker studies for future trials with anti-VEGF therapies. Incorporation of biomarker measurements into this phase II study represent unique strengths of our institution and the NABTC and will enhance our ability to assess the potential efficacy of VEGF Trap in a multidimensional manner. This research is significant because no study has explored the dynamic trend of blood and urine biomarkers in relation to the pharmacology of VEGF Trap and DCE-MRI pharmacodynamic changes though a course of anti- VEGF monotherapy in glioma, explored its possible predictive significance, or evaluated which methodology is the most powerful for defining trends. These studies are critical for establishing which biomarkers are useful in predicting patient response and monitoring treatment progress, as well as forming a baseline for biomarker studies for future trials with anti-VEGF therapies.

描述（由申请人提供）：胶质母细胞瘤是原发性脑肿瘤的最常见类型，并具有严重的预后。尽管最大的治疗包括手术和与化学疗法中位生存期的组合辐射（包括手术和组合辐射）为14个月，不到5％的患者在5年时仍活着。需要采用新的治疗方法来阻止这种毁灭性疾病的进展。内皮增生是胶质母细胞瘤的病理标志，研究表明，促血管生成因子（例如血管内皮生长因子（VEGF））的表达是肿瘤诱导新血管形成的一种机制。 VEGF是一种特定的内皮细胞有丝分裂原，渗透性和生存因子，在包括胶质母细胞瘤在内的几乎所有人类肿瘤中都过表达。 VEGF TRAP是一种重组生产的融合蛋白，它可以清除无VEGF和胎盘生长因子（PLGF），可去除VEGF家族受体的重要配体。在临床前研究中，VEGF陷阱显着提高了带有颅内神经胶质瘤异种移植的小鼠的存活率。已知抗VEGF治疗会改变MRI的对比度增强模式，但尚不清楚这是否准确地反映了肿瘤生物学的变化或将预测长期预后。我们提议研究北美脑肿瘤财团（NABTC）VEGF TRAP TRAP II期临床试验的抗替莫唑胺的胶质母细胞瘤患者的反应生物标志物。为了评估VEGF陷阱的生物学活性并开发反应的预测生物标志物，我们将结合多种药代动力学和药效学参数的测量。游离VEGF和PLGF和VEGF TRAP药理学的血浆和尿液水平将与结局相关，如6个月的无进展生存率（PFS）。将评估来自进步或反应的患者的样本，以评估循环生长因子介导的“肿瘤逃生”​​。将检查预处理肿瘤组织的分子标记和血管性，并将循环内皮细胞测量为反应的潜在决定因素。生物标志物将在治疗前和在序列时间点开始治疗后进行评估，目的是确定肿瘤特异性和循环生物标志物针对内皮细胞的生物标志物与患者结局之间的关联。基于动态对比增强的MRI变化，我们将使用统计和药效学建模将这些度量纳入一个预测的响应模型。这些研究对于确定哪些生物标志物在预测反应和监测治疗进展以及为生物标志物研究的基线研究以后进行抗VEGF疗法的基线至关重要。将生物标志物测量结果纳入这一II阶段研究代表了我们机构和NABTC的独特优势，并将增强我们以多维方式评估VEGF陷阱潜在疗效的能力。这项研究很重要，因为没有研究探索了与VEGF陷阱和DCE-MRI药物学的药理学相关的血液和尿液生物标志物的动态趋势，但通过胶质瘤中的抗VEGF单一疗法疗程，探索了其可能的预测意义，或评估了其可能的预测意义，或评估哪种方法是定义趋势最强大的方法。这些研究对于确定哪些生物标志物可用于预测患者反应和监测治疗进展以及为生物标志物研究进行抗VEGF疗法的生物标志物研究的基线至关重要。