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
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.
|AACR Project GENIE Consortium (2017) AACR Project GENIE: Powering Precision Medicine through an International Consortium. Cancer Discov 7:818-831|
|Sans, Marta; Gharpure, Kshipra; Tibshirani, Robert et al. (2017) Metabolic Markers and Statistical Prediction of Serous Ovarian Cancer Aggressiveness by Ambient Ionization Mass Spectrometry Imaging. Cancer Res 77:2903-2913|
|Robertson, A Gordon; Shih, Juliann; Yau, Christina et al. (2017) Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma. Cancer Cell 32:204-220.e15|
|Yeung, Tsz-Lun; Leung, Cecilia S; Wong, Kwong-Kwok et al. (2017) ELF3 is a negative regulator of epithelial-mesenchymal transition in ovarian cancer cells. Oncotarget 8:16951-16963|
|Gangwar, Ruchika; Meena, Avtar S; Shukla, Pradeep K et al. (2017) Calcium-mediated oxidative stress: a common mechanism in tight junction disruption by different types of cellular stress. Biochem J 474:731-749|
|Cho, Min Soon; Noh, Kyunghee; Haemmerle, Monika et al. (2017) Role of ADP receptors on platelets in the growth of ovarian cancer. Blood 130:1235-1242|
|Harjes, U; Bridges, E; Gharpure, K M et al. (2017) Antiangiogenic and tumour inhibitory effects of downregulating tumour endothelial FABP4. Oncogene 36:912-921|
|Sekihara, Kazumasa; Saitoh, Kaori; Han, Lina et al. (2017) Targeting mantle cell lymphoma metabolism and survival through simultaneous blockade of mTOR and nuclear transporter exportin-1. Oncotarget 8:34552-34564|
|Yang, Wei-Lei; Gentry-Maharaj, Aleksandra; Simmons, Archana et al. (2017) Elevation of TP53 Autoantibody Before CA125 in Preclinical Invasive Epithelial Ovarian Cancer. Clin Cancer Res 23:5912-5922|
|Nagaraja, Archana S; Dood, Robert L; Armaiz-Pena, Guillermo et al. (2017) Adrenergic-mediated increases in INHBA drive CAF phenotype and collagens. JCI Insight 2:|
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