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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA083639-15
Application #
8731077
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
15
Fiscal Year
2014
Total Cost
Indirect Cost
City
Houston
State
TX
Country
United States
Zip Code
77030
Seo, Hyeonglim; Choi, Ikjang; Whiting, Nicholas et al. (2018) Hyperpolarized Porous Silicon Nanoparticles: Potential Theragnostic Material for 29 Si Magnetic Resonance Imaging. Chemphyschem 19:2143-2147
Mitamura, T; Pradeep, S; McGuire, M et al. (2018) Induction of anti-VEGF therapy resistance by upregulated expression of microseminoprotein (MSMP). Oncogene 37:722-731
Yuan, Jiao; Hu, Zhongyi; Mahal, Brandon A et al. (2018) Integrated Analysis of Genetic Ancestry and Genomic Alterations across Cancers. Cancer Cell 34:549-560.e9
Liu, Xiaojun; Jiang, Yingjun; Nowak, Billie et al. (2018) Targeting BRCA1/2 deficient ovarian cancer with CNDAC-based drug combinations. Cancer Chemother Pharmacol 81:255-267
Haemmerle, Monika; Stone, Rebecca L; Menter, David G et al. (2018) The Platelet Lifeline to Cancer: Challenges and Opportunities. Cancer Cell 33:965-983
Allen, Julie K; Armaiz-Pena, Guillermo N; Nagaraja, Archana S et al. (2018) Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction. Cancer Res 78:3233-3242
Umamaheswaran, Sujanitha; Dasari, Santosh K; Yang, Peiying et al. (2018) Stress, inflammation, and eicosanoids: an emerging perspective. Cancer Metastasis Rev 37:203-211
Wang, Jue; Zhao, Wei; Guo, Huifang et al. (2018) AKT isoform-specific expression and activation across cancer lineages. BMC Cancer 18:742
Huang, Yan; Hu, Wei; Huang, Jie et al. (2018) Inhibiting Nuclear Phospho-Progesterone Receptor Enhances Antitumor Activity of Onapristone in Uterine Cancer. Mol Cancer Ther 17:464-473
Yang, Hailing; Mao, Weiqun; Rodriguez-Aguayo, Cristian et al. (2018) Paclitaxel Sensitivity of Ovarian Cancer Can be Enhanced by Knocking Down Pairs of Kinases that Regulate MAP4 Phosphorylation and Microtubule Stability. Clin Cancer Res 24:5072-5084

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