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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：
Panagiotis Z. Anastasiadis
金额：
$ 31.57万
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/8452103
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.

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。