Abstract 3918: Validation of ATX-Red imaging as a potential companion diagnostic for autotaxin-expressing cancers.

Abstract

Abstract Autotaxin (ATX), an autocrine motility factor highly upregulated in metastatic cancer, is a lysophospholipase D that produces the lipid second messenger lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC). Dysregulation of the lysolipid signaling pathway is central to the pathophysiology of numerous cancers, idiopathic pulmonary fibrosis, rheumatoid arthritis, and other inflammatory diseases. Consequently, the ATX/LPA pathway has emerged as an important source of biomarkers and therapeutic targets. Herein we describe development and validation of a fluorogenic analog of LPC (ATX-Red) that enables visualization of ATX activity in vivo. ATX-Red exhibits minimal fluorescence until it is activated by ATX, which significantly increases fluorescence in the near-infrared (NIR) region, the optimal spectral window for in vivo imaging. In mice with ATX-expressing breast cancer orthotopic tumors, ATX activated ATX-Red fluorescence. Injection of ATX-Red into the tail vein of tumor-bearing mice resulted in high fluorescence in the tumor and low fluorescence in healthy tissues. Indeed, tumor fluorescence directly correlated with ATX activity and expression levels. Pretreatment of mice with a known ATX inhibitor markedly and selectively decreased tumor fluorescence. Taken together, the data show that ATX-Red is an effective, non-invasive, and selective tool that enables intravital visualization and quantitation of ATX-expressing tumors and monitoring ATX activity in vivo in real time. ATX-Red has the potential to (1) identify pathological levels of ATX in specific tissues, (2) monitor the time course of therapeutic efficacy of candidate ATX inhibitors in living animal models of human disease, (3) serve as a companion diagnostic for following treatment regimens that target ATX in human patients and (4) serve as a companion diagnostic to select patients that would benefit from ATX-directed therapy. Citation Format: Damian Madan, Colin Ferguson, Won Yong Lee, Charles Testa, Glenn Prestwich. Validation of ATX-Red imaging as a potential companion diagnostic for autotaxin-expressing cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3918. doi:10.1158/1538-7445.AM2013-3918