Mechanism of evasion by ovarian cancers from anti-VEGF therapy

卵巢癌逃避抗 VEGF 治疗的机制

• 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
• 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

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增加无进展生存期 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。