P2 - Targeting DII4-Notch Signaling in Ovarian Cancer

项目SUK/IH/ARID(见说明)： 原发卵巢癌的进行性生长和转移依赖于一种 充足的血液供应(血管生成)。血管内皮生长因子(VEGF)在血管生成中起重要作用 血管生成与卵巢癌的生长和发展。血管内皮细胞生长因子封锁显示出希望 在人类研究中。我们上一次资助期间的临床前和临床结果表明，一种新的 阻断血管内皮生长因子的途径(高亲和力的血管内皮生长因子诱骗受体、血管内皮生长因子陷阱或阿普利赛特)是高度有效的 与紫杉烷化疗联合有效。然而，尽管最初有反应，但大多数患者 最终发展成肿瘤，导致他们死亡，主要是由于药物的开发 抵抗。DII4(delta样配体4)/Notch信号通路最近被证明在一种 在血管生成中的重要作用，包括血管成熟、周细胞募集、分支和细胞 分化、增殖、存活和凋亡。我们的初步数据表明，当抑制DII4时 使用单抗(DII4-mAb或REGN421)与血管内皮生长因子抑制(AfLibercept)相结合，这是 联合用药显著减少了肿瘤负担和腹水，表明这种抗血管生成方案 有望成为一种新的治疗方式。然而，其药效机制尚不完全清楚。 明白了。我们推测，DII4/Notch信号通路在降低DII4/Notch信号通路的 抗血管内皮生长因子单药治疗和同时靶向血管内皮生长因子和DII4/Notch信号通路将增强疗效 抗血管生成治疗。这项提议的总体目标是制定新颖和有效的战略，以 靶向卵巢癌血管生成。在目前的提案中，我们将调查其功能意义 通过检测DII4在卵巢癌中的表达研究DII4/Notch信号通路在卵巢癌中的作用 细胞激活内皮细胞中的Notch信号，而阻断DII4/Notch信号是否与 在目标1中，REGN421解除了对体外血管生成的调控。在目标2中，我们将评估联合应用的疗效 利用AFLibercept和REGN421靶向VEGFA/EGFR/DII4/Notch信号通路的途径 活体原位卵巢癌模型。我们将使用抗DII4进行I/Lb期临床试验 单抗REGN421在AIM 3复发性卵巢癌患者中的应用 是相辅相成的，这项研究的发现应该允许设计新的治疗方法 卵巢癌患者的治疗方法

PROJECT SUK/IH/IARY (See instructions): The progressive growth of primary ovarian cancer and metastasis is dependent on development of an adequate blood supply (angiogenesis). Vascular endothelial growth factor (VEGF) plays a critical role in angiogenesis and consequent ovarian cancer growrth and progression. VEGF blockade has shown promise in human studies. Our pre-clinical and clinical results from the prior funding period demonstrate that a novel approach (high-affinity VEGF decoy receptor, VEGF-Trap or aflibercept) for VEGF blockade was highly effective in combination with taxane chemotherapy. However, despite initial responses, most patients eventually develop tumor progression resulting in their demise, mainly due to the development of drug resistance. The DII4 (delta-like ligand 4)/Notch signaling pathway has recently been shown to play an important role in angiogenesis including vessel maturation, pericyte recruitment, branching and cell differentiation, proliferation, survival and apoptosis. Our preliminary data indicate that when DII4 inhibition using a monoclonal antibody (DII4-mAb or REGN421) was coupled with VEGF inhibition (aflibercept), this combination strikingly reduced tumor burden and ascites, suggesting that this anti-angiogenesis regimen holds promise as a novel therapeutic modality. However, the mechanisms of its potency are not fully understood. We hypothesize that the DII4/Notch signaling pathway plays an important role in reducing the efficacy of anti-VEGF monotherapy and targeting both VEGF and DII4/Notch signaling pathway will enhance anti-angiogenic therapy. The overall goal of this proposal is to develop novel and effective strategies for targeting ovarian cancer angiogenesis. In the current proposal, we will investigate the functional significance of DII4/Notch signaling pathway in ovarian cancer by examining whether DII4 expression in ovarian cancer cells activates Notch signaling in endothelial cells and whether blockade of DII4/Notch signaling with REGN421 deregulates angiogenesis in vitro in Aim 1. In Aim 2, we will assess the efficacy of combinatorial approaches for targeting VEGFA/EGFR/DII4/Notch signaling pathway with aflibercept and REGN421 using in vivo orthotopic ovarian cancer models. We will conduct a Phase I/lb clinical trial using the anti-DII4 monoclonal antibody REGN421 in patients with recurrent ovarian carcinoma in Aim 3. Thus, all three Aims are complementary to each other and findings of this study should allow the design of new therapeutic approaches for women with ovarian cancer