Combining Anti-Invasive and Anti-Angiogenic Therapies for the treatment of GBM

描述(申请人提供)：贝伐单抗的抗血管内皮生长因子抗体疗法提供了显著的临床益处，并日益成为复发性多形性胶质母细胞瘤(GBM)患者的标准护理。不幸的是，贝伐单抗治疗在部分患者中的进展与侵袭性、弥漫性、多灶性疾病复发模式和随后较短的生存间隔相关。使用一种新的原代人GBM异种移植模型，我们复制了类似的表型，在该模型中，贝伐单抗治疗导致胶质瘤侵袭性增加和多灶性疾病复发。我们的初步数据还表明，胶质瘤的侵袭受到Src和PI3激酶信号通路的关键控制。基于这些数据，我们假设，与抗血管内皮生长因子治疗相关的侵袭性增加是由于通过这些途径增加了信号转导。与这一假设一致，我们发现，Src家族激酶(SFK)抑制剂达沙替尼可以阻止贝伐单抗诱导的侵袭性增加和多灶性疾病进展模式。部分基于这些初步数据，我们正在启动一项临床试验，测试贝伐单抗和达沙替尼联合治疗复发的GBM患者。这项应用的重点是严格检测SFK和PI3K信号对贝伐单抗在初次GBM原位异种移植模型和复发GBM患者中的前侵袭效应的影响。具体目的是：1.评价贝伐单抗和达沙替尼对基底膜侵袭的联合作用。2.研究单个SFK和特定的下游信号效应因子在贝伐单抗诱导的侵袭中的作用。3.检测SFK和PI3K抑制对GBM迁移和侵袭的联合作用，以及双重抑制对贝伐单抗反应性的影响。

DESCRIPTION (provided by applicant): Anti-VEGF antibody therapy with bevacizumab provides significant clinical benefit and is increasingly becoming the standard of care for patients with recurrent glioblastoma multiforme (GBM). Unfortunately, progression on bevacizumab therapy in a subset of patients is associated with an aggressive, diffuse, multi- focal disease recurrence pattern and a short subsequent survival interval. Using a novel primary human GBM xenograft model, we have reproduced a similar phenotype in which bevacizumab therapy results in increased glioma invasiveness and in a multi-focal disease recurrence pattern. Our preliminary data also suggest that glioma invasion is critically controlled by Src- and PI3-kinase-depedent signaling pathways. Based on these data, we hypothesize that the increased invasiveness associated with anti-VEGF therapy is due to increased signaling through these pathways. Consistent with this hypothesis, we found that the Src-family kinase (SFK) inhibitor dasatinib can prevent both the increased invasion and the multi-focal disease progression pattern induced by bevacizumab. In part based on these preliminary data, we are initiating a clinical trial testing the combination of bevacizumab and dasatinib in patients with recurrent GBM. The focus of this application is to rigorously examine the influence of SFK and PI3K signaling on the pro-invasive effects of bevacizumab both in primary GBM orthotopic xenograft models and in patients with recurrent GBM. The specific aims are: 1. Assess the combined effects of bevacizumab and dasatinib on GBM invasion. 2. Examine the role of individual SFKs and specific downstream signaling effectors on bevacizumab-induced invasion. 3. Examine the combined effect of SFK and PI3K inhibition on GBM migration and invasiveness, and test the effects of dual inhibition on bevacizumab responsiveness.