Abstract 5170: Monoclonal antibodies to Notch receptors inhibit tumor maintenance

Abstract

Abstract AVEO 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 is 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 various Notch receptors. Characterization of a Notch1-specific monoclonal antibody through cell-based and biochemical studies demonstrated that the antibody bound to the Notch1 ligand binding domain with high affinity, prevented ligand mediated activation of the receptor, and specifically repressed Notch1-dependent signaling with high potency. Mice treated with the Notch1 antibody exhibited altered T cell fate specification and loss of hair pigmentation, as expected for loss of Notch1 function. Significantly, specific inhibition of Notch1 by this antibody did not result in the dose-limiting gut toxicity observed with pan-Notch inhibitors such as gamma-secretase inhibitors. However, strong inhibition of functional angiogenesis was observed upon antibody treatment in both in vitro and in vivo models. The apparent lack of toxicity of this antibody in mouse models suggests that inhibition of Notch1 could be effectively combined with other therapies to enhance anti-angiogenic effects, or to overcome resistance to VEGF/VEGFR inhibition. To identify tumors that are dependent upon tumor autonomous Notch signaling the expression of Notch pathway related genes was correlated with Notch pathway dependence in human cancer cell lines. Active Notch signaling alone did not predict dependence upon Notch, but expression of a single Notch target gene, HeyL, was highly correlated with sensitivity of human cancer cell lines to inhibition of ligand-dependent Notch signal. The utility of this biomarker was further confirmed by the identification of a subset of Kras mutant pancreatic and colon cancer cell lines that were subsequently demonstrated to be highly sensitive to Notch pathway inhibition. Hence, HeyL expression may serve as a predictive biomarker of Notch-dependent tumors. These data support the clinical development of AVEO's humanized Notch antibodies for the treatment of human cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5170.