Microenvironment and Immunology Endothelial ALK1 Is a Therapeutic Target to Block Metastatic Dissemination of Breast Cancer

Exploration of new strategies for the prevention of breast can-cer metastasis is justifiably at the center of clinical attention. In this study, we combined a computational biology approach with mechanism-based preclinical trials to identify inhibitors of acti-vin-like receptor kinase (ALK) 1 as effective agents for blocking angiogenesis and metastasis in breast cancer. Pharmacologic tar-geting of ALK1 provided long-term therapeutic benefit in mouse models of mammary carcinoma, accompanied by strikingly reduced metastatic colonization as a monotherapy or part of combinations with chemotherapy. Gene-expression analysis of breast cancer specimens from a population-based nested case– control study encompassing 768 subjects defined endothelial expression of ALK1 as an independent and highly specific prog-nostic factor for metastatic manifestation, a finding that was corroborated in an independent clinical cohort.Overall, our results suggest that pharmacologic inhibition of endothelial ALK1 con-stitutes a tractable strategy for interfering with metastatic dissem-ination of breast cancer. Cancer Res; 75(12); 2445–56. 2015 AACR