P2 - Targeting DII4-Notch Signaling in Ovarian Cancer

P2 - 靶向卵巢癌中的 DII4-Notch 信号传导

• 批准号: 8731077
• 负责人: ANIL K SOOD
• 金额: $ 18.27万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8731077
• 关键词: Address; Affinity; Angiogenesis Inhibitors; Antibodies; Apoptosis; Ascites; Biological; Biopsy; Blood Vessels; Cancer Model; Cancer Patient; Cell Differentiation process; Clinic; Clinical; Clinical Management; Clinical Trials; Coupled; Data; Development; Disease; Dose; Down-Regulation; Drug Kinetics; Drug resistance; Endothelial Cells; Epidermal Growth Factor Receptor; Epigenetic Process; Funding; Genetic; Goals; Growth; Growth Factor Inhibition; Human; Hypoxia; In Vitro; Instruction; Ligands; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Metastatic Malignant Neoplasm to the Ovary; Modality; Modeling; Molecular; Monoclonal Antibodies; Neoplasm Metastasis; Notch Signaling Pathway; Ovarian; Ovarian Carcinoma; Pathologic Neovascularization; Pathway interactions; Patients; Perfusion; Pericytes; Phase; Physiological; Play; Primary Neoplasm; Prognostic Factor; Progressive Disease; Publishing; Receptor Inhibition; Recurrence; Regimen; Regulation; Resistance; Role; Signal Transduction; Taxane Compound; Therapeutic; Topotecan; Toxic effect; Translations; Tumor Burden; University of Texas M D Anderson Cancer Center; VEGF Trap; VEGFA gene; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vascular blood supply; Woman; Work; angiogenesis; antiangiogenesis therapy; bevacizumab; cancer cell; chemotherapy; combinatorial; density; design; hypoxia inducible factor 1; in vivo; inhibitor/antagonist; insight; non-invasive imaging; notch protein; novel; novel strategies; novel therapeutic intervention; novel therapeutics; pre-clinical; receptor; response; success; taxane; treatment strategy; tumor; tumor growth; tumor microenvironment; tumor progression

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.

项目 SUK/IH/IARY（参见说明）： 原发性卵巢癌和转移的进行性生长取决于 充足的血液供应（血管生成）。血管内皮生长因子（VEGF）在 血管生成和随后的卵巢癌的生长和进展。 VEGF 阻断已显示出希望 在人类研究中。我们之前资助期的临床前和临床结果表明，一种新颖的 VEGF 阻断方法（高亲和力 VEGF 诱饵受体、VEGF-Trap 或阿柏西普）的效果非常好 与紫杉烷类化疗联合使用有效。然而，尽管最初有反应，大多数患者 最终肿瘤进展导致其死亡，这主要是由于药物的开发 反抗。 DII4（δ 样配体 4）/Notch 信号通路最近被证明发挥着重要作用 在血管生成中发挥重要作用，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 DII4 抑制 使用单克隆抗体（DII4-mAb 或 REGN421）结合 VEGF 抑制（阿柏西普），这 组合显着减少了肿瘤负荷和腹水，表明这种抗血管生成方案 有望成为一种新颖的治疗方式。然而，其效力的机制尚不完全 明白了。我们假设 DII4/Notch 信号通路在减少 抗 VEGF 单一疗法以及同时靶向 VEGF 和 DII4/Notch 信号通路的疗效将增强 抗血管生成治疗。该提案的总体目标是制定新颖且有效的策略 靶向卵巢癌血管生成。在当前的提案中，我们将研究功能意义 通过检测 DII4 在卵巢癌中的表达情况来了解 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 信号传导，以及是否阻断 DII4/Notch 信号传导 REGN421 在目标 1 中解除了体外血管生成的调节。在目标 2 中，我们将评估组合的功效 使用阿柏西普和 REGN421 靶向 VEGFA/EGFR/DII4/Notch 信号通路的方法 体内原位卵巢癌模型。我们将使用抗 DII4 进行 I/lb 期临床试验 单克隆抗体 REGN421 在目标 3 中用于治疗复发性卵巢癌患者。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 卵巢癌女性的治疗方法。