Therapeutic Strategies to Target TGF-β in the Treatment of Bone Metastases

Jeroen      T. Buijs; Patricia      Juarez; Theresa      A. Guise

Abstract

Bone is one of the most common organs to be affected in patients with metastatic cancer. These bone metastases are often accompanied by bone destruction, bone fractures, pain, and hypercalcemia. Transforming growth factor-β (TGF-β) is a major bone-derived factor that is released in active form upon osteoclastic bone resorption. TGF-β, in turn, stimulates bone metastatic cells to secrete factors that further drive osteolytic destruction of the bone adjacent to the tumor, categorizing TGF-β as a crucial factor responsible for driving the feed-forward vicious cycle of cancer growth in bone. Moreover, TGF-β activates epithelial-to-mesenchymal transition, increases tumor cell invasiveness and angiogenesis and induces immunosuppression. Blocking the TGF-β signaling pathway to interrupt this vicious cycle between tumor cells and bone offers a promising target for therapeutic intervention to decrease skeletal metastasis. In this review, preclinical and clinical data are evaluated for the potential use of TGF-β inhibitors in clinical practice to treat bone metastases.

Keywords: Antibodies, antisense oligonucleotides, bone metastasis, breast cancer, EMT, prostate cancer, small molecule inhibitors, TGF-β, skeletal metastasis, treat bone metastases, vicious cycle, treat bone metastasis, clinical trials, TGF-β antisense oligonucleotides, c-Jun amino-terminal kinase (JNK)