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性脑肿瘤类型，预后严重。尽管最大的治疗包括手术和放化疗联合治疗，中位生存期为14个月，不到5%的患者在5年存活。需要新的治疗方法来阻止这种毁灭性疾病的发展。内皮细胞增殖是胶质母细胞瘤的病理标志，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机制之一。VEGF是一种特异性的内皮细胞丝裂原、通透性和存活因子，在几乎所有人类肿瘤（包括胶质母细胞瘤）中均有过表达。VEGF Trap是一种重组产生的融合蛋白，它清除游离的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显著提高了颅内胶质瘤移植小鼠的存活率。已知抗vegf治疗可以改变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能否预测长期结果。我们建议在北美脑肿瘤联盟（NABTC） VEGF Trap II期临床试验中研究替莫唑胺耐药胶质母细胞瘤患者的生物标志物反应。为了评估VEGF Trap的生物活性并开发反应的预测性生物标志物，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VEGF、PlGF和VEGF Trap药理学水平将与6个月无进展生存期（PFS）测量的结果相关。将对进展或无反应的患者样本进行循环生长因子介导“肿瘤逃逸”的评估。治疗前的肿瘤组织将被检查分子标记，血管和循环内皮细胞将被测量作为反应的潜在决定因素。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，目的是确定肿瘤特异性和循环生物标志物对内皮细胞活性与患者预后之间的关系。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措施纳入反应的预测模型。这些研究对于确定哪些生物标志物对预测反应和监测治疗进展有用至关重要，同时也为未来抗vegf治疗试验的生物标志物研究形成基线。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潜在功效的能力。这项研究意义重大，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药效学变化的动态趋势，通过一个过程的抗VEGF单药治疗胶质瘤，探索其可能的预测意义，或评估哪种方法是最有效的确定趋势。这些研究对于确定哪些生物标志物在预测患者反应和监测治疗进展方面有用至关重要，并为未来抗vegf治疗试验的生物标志物研究形成基线。

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.