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）：用贝伐单抗的抗VEGF抗体疗法提供了重大的临床益处，并越来越成为复发性胶质母细胞瘤多形胶体（GBM）患者的护理标准。不幸的是，一部分患者的贝伐单抗治疗的进展与侵略性，弥漫性，多局灶性疾病复发模式和随后的生存间隔相关。使用新型的原发性人GBM异种移植模型，我们再现了类似的表型，其中贝伐单抗治疗导致神经胶质瘤的侵袭性增加，并且以多焦点疾病复发模式。我们的初步数据还表明，神经胶质瘤的侵袭受SRC-和PI3-激酶 - depedent信号通路的严格控制。基于这些数据，我们假设与抗VEGF治疗相关的侵入性增加是由于通过这些途径增加信号传导所致。与这一假设一致，我们发现SRC-家庭激酶（SFK）抑制剂达沙替尼可以防止贝伐单抗引起的侵袭增加和多焦点疾病进展模式。部分基于这些初步数据，我们正在启动一项临床试验，该试验测试贝伐单抗和达沙替尼在复发性GBM患者中的组合。该应用的重点是严格检查SFK和PI3K信号传导对贝伐单抗在原代GBM原位异种移植模型以及复发性GBM患者中的影响。具体目的是：1。评估贝伐单抗和达沙替尼对GBM入侵的综合作用。 2。检查单个SFK和特定下游信号效应子对贝伐单抗诱导的侵袭的作用。 3。检查SFK和PI3K抑制对GBM迁移和侵入性的综合作用，并测试双重抑制对贝伐单抗反应性的影响。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的显着延长有关，尽管这种疗法上的最终疾病进展与侵略性疾病和随后的生存间隔相关。该应用的重点是了解分子靶向的疗法是否可以防止抗VEGF疗法的促侵入性作用。最终，该策略可能为这种致命疾病的患者提供额外的生存益处。