Targeting Histone Modifications in Bone and Lung Metastatic Cancers.

Abstract

Breast cancer frequently metastasizes to the bone and lung, but the ability to treat metastatic tumor cells remains a pressing clinical challenge. Histone deacetylases (HDACs) and histone acetyltransferases (HATs) have emerged as promising targets since these enzymes are aberrantly expressed in numerous cancers and regulate the expression of genes that drive tumorigenesis and metastasis. This review focuses on the abnormal expression of histone-modifying enzymes in cancers that have a high tropism for the bone and lung and explores the clinical use of histone deacetylase inhibitors for the treatment and prevention of metastasis to these sites. Preclinical studies have demonstrated that the role for HDACs is highly dependent on tumor type and stage of disease progression. HDAC inhibitors can induce apoptosis, senescence, cell differentiation, and tumor dormancy genes and inhibit angiogenesis, making these promising therapeutics for the treatment of metastatic disease. HDAC inhibitors are already FDA approved for hematologic malignancies and are in clinical trials with standard-of-care chemotherapies and targeted agents for several solid tumors, including cases of metastatic disease. However, these drugs can negatively impact bone homeostasis. Although HDAC inhibitors are not currently administered for the treatment of bone and lung metastatic disease, preclinical studies have shown that these drugs can reduce distant metastasis by targeting molecular factors and signaling pathways that drive tumor cell dissemination to these sites. Thus, HDAC inhibitors in combination with bone protective therapies may be beneficial in the treatment of bone metastatic cancers.