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

Cancer Res. 2015 Jun 15;75(12):2445-56. doi: 10.1158/0008-5472.CAN-14-3706.

Abstract

Exploration of new strategies for the prevention of breast cancer 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 activin-like receptor kinase (ALK) 1 as effective agents for blocking angiogenesis and metastasis in breast cancer. Pharmacologic targeting 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 prognostic factor for metastatic manifestation, a finding that was corroborated in an independent clinical cohort. Overall, our results suggest that pharmacologic inhibition of endothelial ALK1 constitutes a tractable strategy for interfering with metastatic dissemination of breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type II / antagonists & inhibitors*
  • Activin Receptors, Type II / metabolism
  • Animals
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Endothelium / enzymology
  • Female
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Molecular Targeted Therapy
  • Neoplasm Metastasis
  • Protein Kinase Inhibitors / pharmacology*

Substances

  • Protein Kinase Inhibitors
  • ACVRL1 protein, human
  • Activin Receptors, Type II