Therapeutic Potential of Targeting Transforming Growth Factor-beta in Colorectal Cancer: Rational and Progress

Abstract

Background: Colorectal cancer (CRC) is one of the most common types of cancer and is associated with an increasing rate of mortality. Transforming Growth Factor-Beta (TGF-β) is often upregulated in CRC, and appears to play an important role in regulating cell proliferation, migration, immune surveillance, apoptosis, cell differentiation, drug-resistance and many cellular processes that may be involved in CRC, and therefore underscores its potential value as a therapeutic target in the treatment of CRC. An increased expression of the TGF- β pathway has been associated with poor prognosis in several cancer types, including CRC.

Methods: Here, we describe the critical role of the TGF-β pathway in CRC as well as the preclinical and clinical investigations on TGF-β inhibitors, with particular emphasis on recent findings with small-molecule inhibitors in CRC. Several TGF-β inhibitors (e.g., Trabedersen, Galunisertib, Gradalis, PF-03446962, NIS793) have been generated over the past decade for targeting this pathway.

Results: There is accumulating evidence of the therapeutic potential of this and other TGF-β inhibitors for the treatment of other malignancies. These inhibitors might be used in combination with chemotherapy as well as with other biological agents, in order to overcome different resistance mechanisms. However, further studies are needed to identify determinants of the activity of TGF-β inhibitors, through the analysis of genetic and environmental alterations affecting TGF-β and parallel pro-cancer pathways.

Conclusion: These studies will be critical to improving the efficacy and selectivity of current and future anticancer strategies targeting TGF-β.

Keywords: Colorectal cancer; TGF-β inhibitors; TGF-β pathway; anticancer strategies; pro-cancer pathways; therapeutic target..