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）：胶质母细胞瘤是最常见的原发性脑肿瘤类型，预后严重。尽管进行了最大限度的治疗，包括手术和联合放疗与化疗，中位生存期为14个月，不到5%的患者在5年内仍然存活。需要新的治疗方法来阻止这种毁灭性疾病的进展。内皮细胞增殖是胶质母细胞瘤的病理标志，并且研究表明，促血管生成因子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是一种特异性的内皮细胞有丝分裂原、渗透性和存活因子，并且在几乎所有人类肿瘤（包括胶质母细胞瘤）中过表达。VEGF Trap是重组产生的融合蛋白，其清除游离VEGF和胎盘生长因子（PlGF），去除VEGF家族受体的重要配体。在临床前研究中，VEGF Trap显著增加了携带颅内胶质瘤异种移植物的小鼠的存活率。已知抗VEGF治疗可改变MRI上的对比增强模式，但尚不清楚这是否准确反映了肿瘤生物学的变化或是否可预测长期结局。我们建议研究参与北美脑肿瘤联盟（NABTC）VEGF Trap II期临床试验的替莫唑胺耐药胶质母细胞瘤患者的反应生物标志物。为了评估VEGF Trap的生物学活性并开发反应的预测性生物标志物，我们将结合多个药代动力学和药效学参数的测量。游离VEGF和PlGF的血浆和尿液水平以及VEGF捕获物药理学将与如通过6个月无进展生存期（PFS）测量的结果相关。将对进展或无反应患者的样本进行评估，以确定介导“肿瘤逃逸”的循环生长因子。“治疗前的肿瘤组织将被检查的分子标志物和血管和循环内皮细胞将被测量作为反应的潜在决定因素。将在治疗前和治疗开始后的连续时间点评价生物标志物，目的是确定肿瘤特异性和循环生物标志物抗内皮细胞活性与患者结局之间的相关性。基于动态对比增强MRI变化，我们将使用统计学和药效学建模将这些指标纳入缓解预测模型。这些研究对于确定哪些生物标志物可用于预测反应和监测治疗进展以及为未来抗VEGF治疗试验的生物标志物研究形成基线至关重要。将生物标志物测量纳入这项II期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 Trap潜在疗效的能力。本研究具有重要意义，因为没有研究探索血液和尿液生物标志物与VEGF Trap药理学和DCE-MRI药效学变化相关的动态趋势，通过胶质瘤中的抗VEGF单药治疗，探索其可能的预测意义，或评估哪种方法最有效用于定义趋势。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未来抗VEGF治疗试验的生物标志物研究形成基线至关重要。