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.

Public Health Relevance

There are limited options for treating advanced/recurrent ovarian cancer. Anti-angiogenic therapies appear to be one of the most promising for treatment strategies for ovarian and other cancers;however, despite initial responses, most patients eventually develop progressive disease. DII4/Notch signaling is increased in response to elevated VEGF levels and DII4 expression is increased in the tumor vasculature. DII4 blockade especially in combination with anti-VEGF therapy, appears to be a highly promising approach.

National Institute of Health (NIH)
Specialized Center (P50)
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Bottsford-Miller, Justin; Choi, Hyun-Jin; Dalton, Heather J et al. (2015) Differential platelet levels affect response to taxane-based therapy in ovarian cancer. Clin Cancer Res 21:602-10
Sun, Yan; Hu, Limei; Zheng, Hong et al. (2015) MiR-506 inhibits multiple targets in the epithelial-to-mesenchymal transition network and is associated with good prognosis in epithelial ovarian cancer. J Pathol 235:25-36
Wen, Yunfei; Graybill, Whitney S; Previs, Rebecca A et al. (2015) Immunotherapy targeting folate receptor induces cell death associated with autophagy in ovarian cancer. Clin Cancer Res 21:448-59
Previs, Rebecca A; Coleman, Robert L; Harris, Adrian L et al. (2015) Molecular pathways: translational and therapeutic implications of the Notch signaling pathway in cancer. Clin Cancer Res 21:955-61
Zhang, Shu; Lu, Zhen; Unruh, Anna K et al. (2015) Clinically relevant microRNAs in ovarian cancer. Mol Cancer Res 13:393-401
Zhang, Shiwu; Mercado-Uribe, Imelda; Liu, Jinsong (2014) Tumor stroma and differentiated cancer cells can be originated directly from polyploid giant cancer cells induced by paclitaxel. Int J Cancer 134:508-18
Matsuo, Koji; Sheridan, Todd B; Mabuchi, Seiji et al. (2014) Estrogen receptor expression and increased risk of lymphovascular space invasion in high-grade serous ovarian carcinoma. Gynecol Oncol 133:473-9
Liu, Guoyan; Sun, Yan; Ji, Ping et al. (2014) MiR-506 suppresses proliferation and induces senescence by directly targeting the CDK4/6-FOXM1 axis in ovarian cancer. J Pathol 233:308-18
Rich, Thereasa A; Liu, Mei; Etzel, Carol J et al. (2014) Comparison of attitudes regarding preimplantation genetic diagnosis among patients with hereditary cancer syndromes. Fam Cancer 13:291-9
Zhang, S; Mercado-Uribe, I; Xing, Z et al. (2014) Generation of cancer stem-like cells through the formation of polyploid giant cancer cells. Oncogene 33:116-28

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