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

联合抗侵袭和抗血管生成疗法治疗 GBM

基本信息

  • 批准号:
    8452103
  • 负责人:
  • 金额:
    $ 31.57万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-04-01 至 2015-03-31
  • 项目状态:
    已结题

项目摘要

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.
描述(由申请方提供):贝伐珠单抗VEGF抗体治疗提供了显著的临床获益,并日益成为复发性多形性胶质母细胞瘤(GBM)患者的标准治疗。不幸的是,贝伐单抗治疗的进展在一部分患者中与侵袭性、弥漫性、多灶性疾病复发模式和较短的后续生存期相关。使用一种新的原发性人GBM异种移植模型,我们已经复制了一个相似的表型,其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模式。我们的初步数据还表明,胶质瘤的侵袭是严格控制的Src和PI3激酶依赖的信号通路。基于这些数据,我们假设抗VEGF治疗相关的侵袭性增加是由于通过这些途径的信号传导增加。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预防贝伐单抗诱导的侵袭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性GBM患者。本申请的重点是严格检查SFK和PI3K信号传导对贝伐单抗在原发性GBM原位异种移植模型和复发性GBM患者中的促侵袭作用的影响。具体目标是:1.评估贝伐单抗和达沙替尼对GBM侵袭的联合作用。2.检查单个SFK和特定下游信号效应物对贝伐珠单抗诱导的侵袭的作用。3.检查SFK和PI3K抑制对GBM迁移和侵袭性的联合作用,并测试双重抑制对贝伐珠单抗反应性的作用。

项目成果

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Panagiotis Z. Anastasiadis其他文献

Panagiotis Z. Anastasiadis的其他文献

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{{ truncateString('Panagiotis Z. Anastasiadis', 18)}}的其他基金

Role of the Syx-RhoA signaling axis in glioma cell growth and dissemination
Syx-RhoA 信号轴在神经胶质瘤细胞生长和传播中的作用
  • 批准号:
    9923013
  • 财政年份:
    2018
  • 资助金额:
    $ 31.57万
  • 项目类别:
Clinical Relevance of Chromosome 5p/9p/20q/8q Germline Alterations in Glioma
胶质瘤中染色体 5p/9p/20q/8q 种系改变的临床相关性
  • 批准号:
    8729255
  • 财政年份:
    2014
  • 资助金额:
    $ 31.57万
  • 项目类别:
Combining Anti-Invasive and Anti-Angiogenic Therapies for the treatment of GBM
联合抗侵袭和抗血管生成疗法治疗 GBM
  • 批准号:
    8643299
  • 财政年份:
    2010
  • 资助金额:
    $ 31.57万
  • 项目类别:
Combining Anti-Invasive and Anti-Angiogenic Therapies for the treatment of GBM
联合抗侵袭和抗血管生成疗法治疗 GBM
  • 批准号:
    7853714
  • 财政年份:
    2010
  • 资助金额:
    $ 31.57万
  • 项目类别:
Combining Anti-Invasive and Anti-Angiogenic Therapies for the treatment of GBM
联合抗侵袭和抗血管生成疗法治疗 GBM
  • 批准号:
    8039219
  • 财政年份:
    2010
  • 资助金额:
    $ 31.57万
  • 项目类别:
Role of the polarity RhoGEF PLEKHG5 on brain tumor dispersal
极性 RhoGEF PLEKHG5 对脑肿瘤扩散的作用
  • 批准号:
    7873359
  • 财政年份:
    2010
  • 资助金额:
    $ 31.57万
  • 项目类别:
Combining Anti-Invasive and Anti-Angiogenic Therapies for the treatment of GBM
联合抗侵袭和抗血管生成疗法治疗 GBM
  • 批准号:
    8244488
  • 财政年份:
    2010
  • 资助金额:
    $ 31.57万
  • 项目类别:
Role of the polarity RhoGEF PLEKHG5 on brain tumor dispersal
极性 RhoGEF PLEKHG5 对脑肿瘤扩散的作用
  • 批准号:
    8039166
  • 财政年份:
    2010
  • 资助金额:
    $ 31.57万
  • 项目类别:
Cadherin-p120 signaling in motility and invasiveness
钙粘蛋白-p120 运动性和侵袭性信号传导
  • 批准号:
    7096518
  • 财政年份:
    2004
  • 资助金额:
    $ 31.57万
  • 项目类别:
Cadherin-p120 signaling in motility and invasiveness
钙粘蛋白-p120 运动性和侵袭性信号传导
  • 批准号:
    6922806
  • 财政年份:
    2004
  • 资助金额:
    $ 31.57万
  • 项目类别:

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IgG1 抗体的抗原非依赖性血管生成抑制中的性别二态性
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