Mechanism of evasion by ovarian cancers from anti-VEGF therapy

项目总结 大多数被诊断为卵巢癌的妇女都有腹水和播散性疾病。 并在常规铂类化疗后18个月内复发。贝伐单抗是人性化的 该抗体于2014年被批准用于治疗对铂耐药的复发性卵巢癌，并已被 发现与常规化疗联合作为一线治疗可增加无进展生存率 治疗。贝伐单抗中和血管内皮生长因子-A(VEGF)，一种生长因子，具有良好的 刺激内皮细胞存活、迁移和血管形成的既定作用及其原因 腹水堆积。然而，并不是所有的患者都对贝伐单抗有反应，也没有生物标志物可以 可靠地区分可能从这种疗法中受益的患者和不会受益的患者。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 卵巢癌细胞和肿瘤间质成分之间的关系。根据我们的初步研究，我们 假设对贝伐单抗的耐药性可能部分源于卵巢癌细胞 产生被称为外体的小囊泡，这些小泡就像一个“特洛伊木马”，将血管内皮生长因子运送到血管内皮细胞 而不会被贝伐单抗中和。在本项目的目标1中，我们将验证外切体的存在 目的：探讨卵巢癌患者外周血中血管内皮生长因子的信号转导机制。 异种移植模型中外体血管内皮生长因子刺激卵巢肿瘤血管生成和腹水形成的能力。 在目标2中，我们将评估贝伐单抗阻断外切体诱导的卵巢肿瘤血管生成的能力。 和腹水的形成，并评估外体血管内皮生长因子水平与对 贝伐单抗在卵巢癌异种移植模型和卵巢癌患者中的应用。我们的研究解决了关键的 需要生物标志物来指导选择接受贝伐单抗治疗的卵巢癌患者 这是最有益的，也将为设计更有效的抗血管生成疗法提供新的见解。

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.