A Perspective on the Development of TGF-beta Inhibitors for Cancer Treatment

Abstract

Transforming growth factor (TGF)-beta is a secreted multifunctional cytokine that signals via plasma membrane TGF-beta type I and type II receptors and intercellular SMAD transcriptional effectors. Aberrant inter- and intracellular TGF-beta signaling can contribute to cancer progression. In normal cells and early stages of cancer, TGF-beta can stimulate epithelial growth arrest and elicit a tumor suppressor function. However, in late stages of cancer, when the cytostatic effects of TGF-beta in cancer cells are blocked, TGF-beta signaling can act as tumor promoter by its ability to stimulate epithelial-to-mesenchymal transition of cancer cells, by stimulating angiogenesis, and by promoting evasion of immune responses. In this review, we will discuss the rationale and challenges of targeting TGF-beta signaling in cancer and summarize the clinical status of TGF-beta signaling inhibitors that interfere with TGF-beta bioavailability, TGF-beta/receptor interaction, or TGF-beta receptor kinase function. Moreover, we will discuss targeting of TGF-beta signaling modulators and downstream effectors as well as alternative approaches by using promising technologies that may lead to entirely new classes of drugs.