Mechanism of evasion by ovarian cancers from anti-VEGF therapy

项目摘要 大多数被诊断为卵巢癌的妇女表现为腹水和播散性疾病 常规铂类化疗后18个月内复发。贝伐单抗是一种人源化 2014年批准用于治疗铂耐药复发性卵巢癌的抗体， 发现与常规化疗联合作为一线治疗时可增加无进展生存期 治疗贝伐单抗可中和血管内皮生长因子-A（VEGF），这是一种生长因子， 在刺激内皮细胞存活、迁移和血管形成中的作用， 腹水积聚。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治疗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 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， 假设对贝伐单抗的抗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，作为“特洛伊木马”将VEGF输送到内皮细胞 而不被贝伐单抗中和。在本项目的目标1中，我们将验证外泌体的存在， VEGF在卵巢癌患者中的表达，确定外泌体VEGF的信号传导机制，并评估 外来体VEGF刺激异种移植模型中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 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 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.