Predictive Markers of Glioblastoma Response to VEGF Trap

描述(申请人提供)：胶质母细胞瘤是最常见的原发脑肿瘤类型，预后严重。尽管最大限度的治疗包括手术和放化疗相结合，中位生存期为14个月，不到5%的患者在5年后仍能存活。需要新的治疗方法来阻止这种毁灭性疾病的发展。血管内皮细胞增殖是胶质母细胞瘤的病理标志，研究表明血管内皮生长因子等促血管生成因子的表达是肿瘤诱导新生血管形成的机制之一。血管内皮生长因子是一种特异的内皮细胞有丝分裂原、通透性和生存因子，在包括胶质母细胞瘤在内的几乎所有人类肿瘤中都有过表达。血管内皮生长因子陷阱是一种重组表达的融合蛋白，可清除游离的血管内皮生长因子和胎盘生长因子，去除血管内皮生长因子家族受体的重要配体。在临床前研究中，血管内皮生长因子陷阱显著提高了携带异种脑胶质瘤小鼠的存活率。众所周知，抗血管内皮生长因子治疗会改变MRI上的增强模式，但目前尚不清楚这是否准确地反映了肿瘤生物学的变化，或者是否可以预测长期结果。我们建议在北美脑瘤联合会(NABTC)的VEGFTrap II期临床试验中研究耐替莫唑胺的胶质母细胞瘤患者的反应生物标志物。为了评估血管内皮生长因子陷阱的生物学活性并开发可预测的反应生物标志物，我们将结合多种药代动力学和药效学参数的测量。血浆和尿液中游离的血管内皮生长因子和PlGF水平以及血管内皮生长因子陷阱的药理作用将与以6个月无进展生存期(PFS)衡量的预后相关。对进展或无反应的患者的样本将进行评估，以确定是否有循环生长因子调节“肿瘤逃逸”。治疗前的肿瘤组织将被检查分子标志物和血管，循环内皮细胞将被测量为潜在的反应决定因素。生物标志物将在治疗前和治疗开始后的连续时间点进行评估，目的是确定抗内皮细胞活性的肿瘤特异性和循环生物标志物与患者预后之间的关联。基于动态增强MRI的变化，我们将使用统计学和药效学模型将这些措施合并到反应的预测模型中。这些研究对于确定哪些生物标记物在预测反应和监测治疗进展中是有用的，以及为未来抗血管内皮生长因子治疗试验的生物标记物研究形成基线至关重要。将生物标记物测量纳入这项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。这项研究具有重要意义，因为还没有研究通过抗VEGF单药治疗脑胶质瘤的一个疗程来探索血和尿生物标记物的动态趋势与VEGF Trap和DCE-MRI药效学变化的关系，探索其可能的预测意义，或评估哪种方法是确定趋势的最有效方法。这些研究对于确定哪些生物标记物在预测患者反应和监测治疗进展方面是有用的，以及为未来抗血管内皮生长因子治疗试验的生物标记物研究形成基线至关重要。

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.