Clinical development of therapies targeting TGF beta: current knowledge and future perspectives

Transforming growth factor beta (TGFO) is a pleiotropic cytokine that plays a key role in both physiologic and pathologic conditions, including cancer. Importantly, TGFO can exhibit both tumor-suppressive and oncogenic functions. In normal epithelial cells TGFO acts as an antiproliferative and differentiating factor, whereas in advanced tumors TGFO can act as an oncogenic factor by creating an immune-suppressive tumor microenvironment, and inducing cancer cell proliferation, angiogenesis, invasion, tumor progression, and metastatic spread. A wealth of preclinical findings have demonstrated that targeting TGFO is a promising means of exerting antitumor activity. Based on this rationale, several classes of TGFO inhibitors have been developed and tested in clinical trials, namely, monoclonal, neutralizing, and bifunctional antibodies; antisense oligonucleotides; TGFO-related vaccines; and receptor kinase inhibitors. It is now >15 years since the first clinical trial testing an anti-TGFO agent was engaged. Despite the promising preclinical studies, translation of the basic understanding of the TGFO oncogenic response into the clinical setting has been slow and challenging. Here, we review the conclusions and status of all the completed and ongoing clinical trials that test compounds that inhibit the TGFO pathway, and discuss the challenges that have arisen during their clinical development. With none of the TGFO inhibitors evaluated in clinical trials approved for cancer therapy, clinical development for TGFO blockade therapy is primarily oriented toward TGFO inhibitor combinations. Immune checkpoint inhibitors are considered candidates, albeit with efficacy anticipated to be restricted to specific populations. In this context, we describe current efforts in the search for biomarkers for selecting the appropriate cancer patients who are likely to benefit from anti-TGFO therapies. The knowledge accumulated during the last 15 years of clinical research in the context of the TGFO pathway is crucial to design better, innovative, and more successful trials.