Abstract 2990: Notch1 monoclonal antibody inhibits tumor growth and modulates angiogenesis

• Published in: Cancer research (Chicago, Ill.) Vol. 74; no. 19_Supplement; p. 2990
• Main Authors: Okamura, Heidi, Proia, Theresa, Bell, Alisa, Liu, Qing, Siddiquee, Zakir, Lin, Jie, Gyuris, Jeno
• Format: Journal Article
• Language: English
• Published: 01.10.2014
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2014-2990

Abstract AVEO Oncology has developed a series of inducible mouse models of cancer, which through the preservation of critical tumor/stromal interactions, facilitate identification of cell-surface and secreted proteins that represent viable targets for therapeutic antibodies and other biologics. Functional genetic screens performed in vivo in these models identified the Notch pathway as a critical regulator of tumor maintenance. This finding was consistent with emerging evidence that activation of Notch signaling via receptor point mutation, receptor amplification, and elevated receptor and ligand expression, plays a key role in various human cancers. Moreover, the Notch pathway controls diverse aspects of tumorigenesis and tumor maintenance, regulating tumor autonomous processes and interactions with the microenvironment, including angiogenesis. To further understand the role of the Notch pathway in tumor maintenance, and to assess the therapeutic potential of targeting the Notch pathway in cancer, we have generated monoclonal antibodies that inhibit the Notch1 receptor. Characterization of monoclonal antibodies targeting Notch1 through cell-based and biochemical studies demonstrated that the Notch1 monoclonal antibody bound with high affinity and high specificity to the Notch1 receptor, prevented ligand-mediated activation of the target receptor, and specifically repressed Notch-dependent signaling with high potency. Significantly, specific inhibition by the Notch1 monoclonal antibody did not result in the dose-limiting gut toxicity observed with Notch1 mAb resulted in tumor inhibition that was accompanied by increased vascular density, inhibition of Notch target gene expression, and increased expression of angiogenesis-related genes, consistent with expected changes resulting from Notch1/Dll4 pathway inhibition. In addition, several tumor models treated in combination with Notch1 mAb and an investigational VEGF pathway inhibitor, tivozanib, demonstrated increased tumor inhibition compared to either agent alone. Interestingly, combination treatment resulted in decreased vascular density and downregulated expression of angiogenesis genes, similar to treatment with VEGF inhibitor alone. Collectively, our work suggests that combination therapy of Notch1 antibodies with VEGF inhibitors should be evaluated as a potential viable therapeutic option for VEGF-resistant tumors. Citation Format: Heidi Okamura, Theresa Proia, Alisa Bell, Qing Liu, Zakir Siddiquee, Jie Lin, Jeno Gyuris. Notch1 monoclonal antibody inhibits tumor growth and modulates angiogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2990. doi:10.1158/1538-7445.AM2014-2990