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

Sara I Cunha, Matteo Bocci, John Lövrot, Nikolas Eleftheriou, Pernilla Roswall, Eugenia Cordero, Linda Lindström, Michael Bartoschek, B Kristian Haller, R Scott Pearsall, Aaron W Mulivor, Ravindra Kumar, Christer Larsson, Jonas Bergh, Kristian Pietras

Research output: Contribution to journalArticlepeer-review

38 Citations (SciVal)

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. Cancer Res; 75(12); 2445-56. ©2015 AACR.
Original languageEnglish
Pages (from-to)2445-2456
JournalCancer Research
Volume75
Issue number12
DOIs
Publication statusPublished - 2015

Subject classification (UKÄ)

  • Cancer and Oncology

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