TGFß-Directed Therapeutics: 2020.

ABSTRACT

The transforming growth factor-beta (TGFß) pathway is essential during embryo development and in maintaining normal homeostasis. During malignancy, the TGFß pathway is co-opted by the tumor to increase fibrotic stroma, to promote epithelial to mesenchymal transition increasing metastasis and producing an immune-suppressed microenvironment which protects the tumor from recognition by the immune system. Compelling preclinical data demonstrate the therapeutic potential of blocking TGFß function in cancer. However, the TGFß pathway cannot be described as a driver of malignant disease. Two small molecule kinase inhibitors which block the serine-threonine kinase activity of TGFßRI on TGFßRII, a pan-TGFß neutralizing antibody, a TGFß trap, a TGFß antisense agent, an antibody which stabilizes the latent complex of TGFß and a fusion protein which neutralizes TGFß and binds PD-L1 are in clinical development. The challenge is how to most effectively incorporate blocking TGFß activity alone and in combination with other therapeutics to improve treatment outcome.