Study Finds ALK1 May Be a Therapeutic Target for Metastatic Breast Cancer
A study investigating the process involved in metastatic breast cancer has found that patients with high levels of the protein activin-like receptor kinase (ALK) 1 in the blood vessels of their tumors were more likely to develop metastatic disease than patients without endothelial expression of ALK1. ALK 1 is a type 1 receptor in the large TGF-beta family expressed selectively by endothelial cells. Inhibiting the ALK1 pathway may be a possible new target for the treatment of metastatic breast cancer, according to the research findings. The study by Cunha et al is published in Cancer Research.
Study Methodology
The researchers combined a computational biology approach with mechanism-based preclinical trials to identify inhibitors of ALK1 as effective agents for blocking angiogenesis and metastasis in breast cancer. To understand the role of ALK1 in breast cancer metastasis and test an ALK1 inhibitor, the researchers used multiple advanced genetically engineered mouse models of breast cancer; tumor samples from 768 patients in a population-based, nested case control study; and breast cancer gene-expression data from The Cancer Genome Atlas.
Study Findings
Using the mouse models of breast cancer, the researchers found that a mouse version of the ALK1 inhibitor dalantercept (ACE-041) prevented metastatic dissemination and that combination therapy with dalantercept and docetaxel was effective in preventing the spread of the primary breast tumor to the lungs.
After analyzing the gene-expression patterns in the tumors of the 768 patients, the researchers found that expression of ALK1 was significantly associated with the incidence of metastatic disease. To further validate their findings, the researchers then analyzed breast cancer gene expression from The Cancer Genome Atlas and found that ALK1 expression correlated with the expression of well-known endothelial markers and that higher levels of ALK1 expression were an independent prognostic factor for poor survival in patients with breast cancer.
“Taken together, our mechanism-based therapeutic studies, combined with gene expression analysis of patient specimens designed to investigate prometastatic factors, thus strongly support further development of ALK1-targeting agents, such as dalantercept and PF-03446962, as clinically tractable combination partners for chemotherapy to reduce the incidence of distant metastases in breast cancer,” concluded the study authors.
Kristian Pietras, PhD, of Lund University, is the corresponding author of this study.
Dr. Pietras has ownership interest in a patent pertaining to ALK1 antagonism held by the Ludwig Institute for Cancer Research Ltd and licensed to Acceleron Pharma. Ravindra Kumar, MD, is a Chief Scientific Officer and has ownership interest, including patents, in Acceleron Pharma. The other study authors reported no potential conflicts of interest.
Funding for this study was provided by the European Research Council; the Swedish Research Council; the STARGET Consortium; BioCARE; Lund University; BRECT; the Karolinska Institutet and the Stockholm County Council; and the Radiumhemmet, Karolinska Instituet, and Karolinska University Hospital.
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