Modulation of Resistance to antiangiogenic therapy: A clinical trial with correla

描述(申请人提供)：血管增殖是胶质母细胞瘤的病理特征，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。抗血管生成治疗被证明能迅速降低血管通透性，减轻脑水肿，延长一些复发胶质母细胞瘤患者的无进展生存期(PFS)。然而，具有内在耐药性的患者不能从抗血管内皮生长因子治疗中受益，而那些最初有反应的患者获得的耐药性限制了该方法的长期有效性。抗血管内皮生长因子治疗耐药的机制可能很多，但最近的报道表明，骨髓来源的细胞(BMDCs)可能是耐药的重要介质。我们已经开发了一种新的临床试验，旨在潜在地调节胶质母细胞瘤对贝伐单抗的耐药性。复发的胶质母细胞瘤患者将随机接受标准剂量的贝伐单抗或小剂量的贝伐单抗联合洛莫司汀治疗，以最大限度地将药物输送到肿瘤。较低剂量的贝伐单抗将被用于改善药物输送和防止或延缓严重缺氧的发展，我们已经证明，严重缺氧是接受慢性抗血管内皮生长因子治疗的胶质母细胞瘤肿瘤的一个显著特征。为了评估胶质母细胞瘤对抗血管内皮生长因子治疗的敏感性和耐药性的潜在调节因素，本试验将评估标准剂量与低剂量ARM中循环趋化因子和髓系细胞的变化。在目标1中，我们将确定单核细胞和粒细胞趋化因子的基线水平是否可以预测抗血管内皮生长因子治疗的反应。目的2将评估抗血管内皮生长因子治疗后髓系细胞的募集情况。目的3将评估复发性胶质母细胞瘤手术时血浆趋化因子、髓样细胞渗入胶质母细胞瘤标本的数量和血管增殖的组织学标志物之间的关系。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方面是有用的，以及为未来纳入针对髓系细胞群体的治疗的试验形成基线至关重要。将生物标记物测量纳入这项第二阶段研究代表了我们机构的独特优势，并将增强我们以多维方式评估替代贝伐单抗给药计划的潜在疗效的能力。 公共卫生相关性：尽管在接受抗血管生成治疗的复发性胶质母细胞瘤患者中看到了有希望的放射学反应，但这种治疗的长期有效性仍然受到耐药性发展的限制。我们的临床试验将试图调节和延缓抗血管内皮生长因子治疗耐药性的发展，同时探索血浆趋化因子及其招募的髓系细胞作为治疗敏感性和耐药性的预测标记物。

DESCRIPTION (provided by applicant): Vascular 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. Antiangiogenic therapy has been shown to rapidly decrease vascular permeability, reduce cerebral edema, and prolong progression free survival (PFS) in some patients with recurrent glioblastoma. However, patients with intrinsic resistance do not benefit from anti-VEGF therapy and those that initially respond acquire resistance limiting the long-term effectiveness of this approach. The mechanisms of resistance to anti-VEGF therapy are potentially many but recent reports suggest that bone marrow derived cells (BMDCs) may be important mediators of resistance. We have developed a novel clinical trial designed to potentially modulate the development of glioblastoma resistance to bevacizumab. Patients with recurrent glioblastoma will be randomized to receive standard dose bevacizumab or low-dose bevacizumab combined with lomustine given on day 3 during the "normalization window" to maximize drug delivery to tumor. The lower dose of bevacizumab will be utilized to both improve drug delivery and to prevent or delay the development of severe hypoxia which we have shown to be a prominent feature of glioblastoma tumors treated with chronic anti-VEGF therapy. To evaluate potential modulators of glioblastoma sensitivity and resistance to anti-VEGF therapy, this trial will assess changes in circulating chemokines and myeloid cells in the standard dose versus low dose arms. In Aim 1, we will determine if baseline plasma levels of monocytic and granulocytic chemokines are predictive of response to anti-VEGF therapy. Aim 2 will assess the recruitment of myeloid cells following anti-VEGF therapy. Aim 3 will assess the association between plasma chemokines, the number of myeloid cells infiltrated into glioblastoma samples and histologic markers of vascular proliferation at the time of surgery for recurrent glioblastoma. 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 future trials that incorporate therapies targeting myeloid cell populations. Inclusion of biomarker measurements into this phase II study represent unique strengths of our institution and will enhance our ability to assess the potential efficacy of an alternative bevacizumab dosing schedule in a multidimensional manner. PUBLIC HEALTH RELEVANCE: Despite the promising radiographic responses seen in patients with recurrent glioblastoma treated with antiangiogenic therapy, the long term effectiveness of this therapy remains limited by the development of resistance. Our clinical trial will attempt to modulate and delay the development of resistance to anti-VEGF therapy while exploring plasma chemokines and the myeloid cells they recruit as predictive markers of sensitivity and resistance to therapy.