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：
7853714
负责人：
Panagiotis Z. Anastasiadis
金额：
$ 34.55万
依托单位：
MAYO CLINIC JACKSONVILLE
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

来源：
https://reporter.nih.gov/project-details/7853714
关键词：
1-Phosphatidylinositol 3-Kinase Angiogenesis Inhibition Angiogenic Factor Animal Model Animals Antibody Therapy Cells Characteristics Clinic Clinical Clinical Trials Combined Modality Therapy Dasatinib Data Diffuse Disease Disease Progression Epidermal Growth Factor Receptor Failure Family Glioblastoma Glioma Gliomagenesis Human Hypoxia In Vitro Individual Infiltration Invaded Malignant - descriptor Malignant Glioma Mediator of activation protein Molecular Molecular Genetics Monoclonal Antibodies Mus Nature North Central Cancer Treatment Group PDGFRB gene Pathway interactions Patients Pattern Phenotype Progression-Free Survivals Proto-Oncogene Proteins c-akt Publishing Radiation Therapy Oncology Group Receptor Protein-Tyrosine Kinases Recurrence Reporting Resistance Resistance development Role Sampling Signal Pathway Signal Transduction Testing Therapeutic Tumor Biology Tumor Cell Invasion Vascular Endothelial Growth Factors Xenograft Model Xenograft procedure angiogenesis base bevacizumab catenin p120ctn protein combinatorial design disease natural history human BCAR1 protein human FRAP1 protein humanized monoclonal antibodies improved in vivo inhibitor/antagonist insight kinase inhibitor meetings member migration neoplastic cell novel novel strategies prevent public health relevance response src-Family Kinases standard of care tumor tumor progression

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. PUBLIC HEALTH RELEVANCE: Anti-VEGF therapy is associated with significant prolongation in progression-free survival in patients with recurrent GBM, although ultimate disease progression on this therapy is associated with aggressive disease and a short subsequent survival interval. The focus of this application is to understand whether molecularly-targeted therapies can prevent the pro-invasive effects of anti-VEGF therapy. Ultimately this strategy may provide additional survival benefit for patients with this deadly disease.

描述（由申请人提供）：使用贝伐珠单抗进行抗 VEGF 抗体治疗可提供显着的临床益处，并日益成为复发性多形性胶质母细胞瘤 (GBM) 患者的护理标准。不幸的是，部分患者接受贝伐珠单抗治疗后的进展与侵袭性、弥漫性、多灶性疾病复发模式和随后较短的生存间隔有关。使用新型原发性人类 GBM 异种移植模型，我们重现了类似的表型，其中贝伐单抗治疗导致神经胶质瘤侵袭性增加和多病灶疾病复发模式。我们的初步数据还表明，神经胶质瘤侵袭受到 Src 和 PI3 激酶依赖性信号通路的关键控制。基于这些数据，我们假设与抗 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所致。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，测试贝伐珠单抗和达沙替尼联合治疗复发性 GBM 患者。本申请的重点是在原发性 GBM 原位异种移植模型和复发性 GBM 患者中严格检查 SFK 和 PI3K 信号传导对贝伐单抗促侵袭作用的影响。具体目标是： 1. 评估贝伐珠单抗和达沙替尼对 GBM 侵袭的联合作用。 2. 检查单个 SFK 和特定下游信号传导效应器对贝伐珠单抗诱导的侵袭的作用。 3.考察SFK和PI3K抑制对GBM迁移和侵袭的联合作用，并测试双重抑制对贝伐珠单抗反应性的影响。公共卫生相关性：抗 VEGF 治疗与复发性 GBM 患者的无进展生存期显着延长相关，尽管该治疗的最终疾病进展与侵袭性疾病和随后的生存间隔较短有关。该应用的重点是了解分子靶向治疗是否可以阻止抗 VEGF 治疗的促侵袭作用。最终，这种策略可能会为患有这种致命疾病的患者提供额外的生存益处。