P2 - Targeting DII4-Notch Signaling in Ovarian Cancer

项目SUK/IH/IARY（参见说明）： 原发性卵巢癌的进行性生长和转移依赖于肿瘤的发生， 充足的血液供应（血管生成）。血管内皮生长因子（VEGF）在肿瘤的发生发展中起着重要作用。 血管生成和随后的卵巢癌生长和进展。VEGF阻断已显示出希望 在人类研究中。我们的临床前和临床结果从以前的资助期表明，一种新的 用于VEGF阻断的方法（高亲和力VEGF诱饵受体、VEGF-Trap或阿柏西普）是高度有效的。 与紫杉烷化疗联合有效。然而，尽管最初的反应，大多数患者 最终发展成肿瘤进展，导致其死亡，这主要是由于药物的开发， 阻力DII 4（δ样配体4）/Notch信号通路最近已被证明发挥作用， 在血管生成包括血管成熟、周细胞募集、分支和细胞增殖中起重要作用 分化、增殖、存活和凋亡。我们的初步数据表明，当DII 4抑制 使用单克隆抗体（DII 4-mAb或REGN 421）与VEGF抑制（阿柏西普）偶联， 联合用药显著降低了肿瘤负荷和腹水，表明这种抗血管生成方案 有望成为一种新的治疗方式。但其作用机制尚不完全清楚， 明白我们假设DII 4/Notch信号通路在降低细胞凋亡中起重要作用。 抗VEGF单一疗法和靶向VEGF和DII 4/Notch信号传导途径的功效将增强 抗血管生成治疗该提案的总体目标是制定新颖有效的战略， 靶向卵巢癌血管生成。在当前的提案中，我们将研究 卵巢癌中DII 4/Notch信号通路的研究 细胞激活内皮细胞中的Notch信号传导，以及阻断DII 4/Notch信号传导是否与 在Aim 1中，REGN 421在体外解除血管生成调节。在目标2中，我们将评估组合的功效。 使用阿柏西普和REGN 421靶向VEGFA/EGFR/DII 4/Notch信号通路的方法， 体内原位卵巢癌模型。我们将使用抗DII 4抗体进行I期/Ib临床试验。 目标3中复发性卵巢癌患者的单克隆抗体REGN 421。因此，所有三个目标 是相互补充的，这项研究的结果应该允许设计新的治疗方法。 卵巢癌的治疗方法

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