Mechanism of evasion by ovarian cancers from anti-VEGF therapy

卵巢癌逃避抗 VEGF 治疗的机制

基本信息

批准号：
9302312
负责人：
Honami Naora
金额：
$ 36.6万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9302312
关键词：
Address Angiogenic Factor Ascites Benchmarking Biological Assay Biological Markers Body Fluids Cancer Patient Cancer cell line Carcinomatosis Cell Survival Clinical Clinical Management Diagnosis Disease Electron Microscopy Endothelial Cells Equus caballus FDA approved Goals Growth Factor In Vitro Malignant neoplasm of ovary Measures Mediating Membrane Monitor Normal Cell Patient Selection Patients Peritoneal Platinum Play Progression-Free Survivals Proteins RNA Recurrence Regulation Relapse Reporting Research Personnel Resistance Role Signal Pathway Signal Transduction Specimen Stromal Cells Tube Tumor Angiogenesis VEGFA gene Vesicle Woman Xenograft Model base bevacizumab cancer cell cell type chemotherapy design exosome experience humanized antibody humanized monoclonal antibodies in vivo Model insight migration multidisciplinary neutralizing antibody neutralizing monoclonal antibodies ovarian neoplasm prototype response stem structural biology targeted agent taxane tumor tumor growth tumor progression

项目摘要

PROJECT SUMMARY The majority of women who are diagnosed with ovarian cancer present with ascites and disseminated disease and relapse within 18 months after conventional platinum-based chemotherapy. Bevacizumab is a humanized antibody that was approved in 2014 for treating platinum-resistant recurrent ovarian cancer and has also been found to increase progression-free survival when combined with conventional chemotherapy as front-line treatment. Bevacizumab neutralizes vascular endothelial growth factor-A (VEGF), a growth factor that has well- established roles in stimulating endothelial cell survival, migration and vessel formation and also causes ascites accumulation. However, not all patients respond to bevacizumab and there are no biomarkers that can reliably distinguish patients who are likely to benefit from this therapy from those who will not. We have extensively investigated the mechanisms that control ovarian tumor progression, in particular the interactions between ovarian cancer cells and constituents of the tumor stroma. Based on our preliminary studies, we hypothesize that resistance to bevacizumab might stem in part from the ability of ovarian cancer cells to produce small vesicles called exosomes that act as a `Trojan Horse' to deliver VEGF to endothelial cells without being neutralized by bevacizumab. In Aim 1 of this project, we will validate the presence of exosomal VEGF in ovarian cancer patients, determine the signaling mechanism of exosomal VEGF, and evaluate the ability of exosomal VEGF to stimulate ovarian tumor angiogenesis and ascites formation in xenograft models. In Aim 2, we will evaluate the ability of bevacizumab to block exosome-induced ovarian tumor angiogenesis and ascites formation, and evaluate the relationship between levels of exosomal VEGF and responses to bevacizumab in ovarian cancer xenograft models and ovarian cancer patients. Our study addresses the critical need for biomarkers that could guide the selection of ovarian cancer patients for whom bevacizumab treatment is most beneficial and will also provide new insights for designing more effective anti-angiogenic therapies.

项目概要大多数被诊断患有卵巢癌的女性会出现腹水和播散性疾病传统铂类化疗后 18 个月内复发。贝伐珠单抗是一种人源化该抗体于 2014 年被批准用于治疗铂耐药复发性卵巢癌，发现与常规化疗联合作为一线疗法可提高无进展生存期治疗。贝伐珠单抗可中和血管内皮生长因子-A (VEGF)，这是一种具有良好作用的生长因子。在刺激内皮细胞存活、迁移和血管形成中已确定的作用，并且还导致腹水积聚。然而，并非所有患者都对贝伐珠单抗有反应，并且没有生物标志物可以可靠地区分可能从该疗法中受益的患者与不会受益的患者。我们有广泛研究了控制卵巢肿瘤进展的机制，特别是相互作用卵巢癌细胞和肿瘤基质成分之间的关系。根据我们的初步研究，我们假设对贝伐珠单抗的耐药性可能部分源于卵巢癌细胞的能力产生称为外泌体的小囊泡，充当“特洛伊木马”将 VEGF 传递至内皮细胞不被贝伐珠单抗中和。在该项目的目标 1 中，我们将验证外泌体的存在卵巢癌患者中的 VEGF，确定外泌体 VEGF 的信号机制，并评估外泌体 VEGF 在异种移植模型中刺激卵巢肿瘤血管生成和腹水形成的能力。在目标 2 中，我们将评估贝伐珠单抗阻断外泌体诱导的卵巢肿瘤血管生成的能力和腹水形成，并评估外泌体 VEGF 水平与对腹水的反应之间的关系贝伐单抗在卵巢癌异种移植模型和卵巢癌患者中的作用。我们的研究解决了关键问题需要可以指导选择接受贝伐珠单抗治疗的卵巢癌患者的生物标志物是最有益的，也将为设计更有效的抗血管生成疗法提供新的见解。