Abstract 1681: Inhibition of tumor growth in vivo through neutralization of the interaction of MCAM with laminin alpha 4

Abstract

Melanoma cell adhesion molecule (MCAM/CD146) is highly expressed on a subset of many tumor types including melanoma and glioblastoma, and expression of MCAM correlates with enhanced cellular invasion, increased metastasis, and poor patient prognosis. The expression of MCAM on tumor cells confers unique migratory and adhesion capacity, which, if specifically targeted, could result in interruption of multiple biological processes required for tumor growth and spread. Although a role for MCAM in tumor progression has long been appreciated, the unidentified ligand for MCAM precluded the development of targeted approaches to inhibit extracellular interactions mediated by MCAM. Recently, we identified the MCAM ligand as laminin alpha 4. Laminin alpha 4 is present within the extracellular matrix of the tumor in addition to the vasculature throughout the body, providing an adhesive substrate for MCAM expressing tumor cells both within the tumor microenvironment and the blood vessels. The presence of laminin alpha 4 within the tumor and the vasculature may allow for a biological interaction by which MCAM mediated adhesion could be involved in both the homotypic aggregation required for tumor growth, in addition to the vascular adhesion required for the processes of metastasis and angiotropism. We generated monoclonal antibodies that bind to the epitope required for MCAM interactions with laminin alpha 4. Such antibodies entirely abrogate interactions of the tumor cell with laminin alpha 4 in vitro. Furthermore, we characterized the inhibition of tumor growth in vivo mediated by neutralization of MCAM/laminin alpha 4 interactions. Notably, tumor growth was delayed by blockade of MCAM, but required inhibition of both the MCAM expressed by the tumor, as well as vascular MCAM. We further characterize the unique pattern of MCAM expression on tumor cells within the perivascular extracellular matrix in human tumors, which suggest that these interactions are involved in human disease pathogenesis. Thus, antibodies neutralizing the interaction between MCAM and laminin alpha 4 have potential to inhibit a critical molecular interaction used by myriad tumor types.

Citation Format: Ken Flanagan, Lauri W. Li, Carlos Lorenzana, Stephen J. Tam, Yue Liu, Philip J. Dolan, Lana Alexander, Josh Salmans, Robin M. Barbour, Jeffrey N. Higaki, Tarlochan Nijjar, Wagner Zago, Ted A. Yednock, Gene Kinney. Inhibition of tumor growth in vivo through neutralization of the interaction of MCAM with laminin alpha 4. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1681. doi:10.1158/1538-7445.AM2015-1681