Targeting Aberrant TGF-β Signaling in Pre-Clinical Models of Cancer

Anna   Alexeyevna   Mourskaia; Jason   Jonathan   Northey; Peter   Michael   Siegel

doi:10.2174/187152007781668689

Abstract

The TGF-β signaling pathway is central to the control of diverse biological processes including cellular proliferation, cell survival, apoptosis, extracellular matrix deposition/remodeling, migration, invasion and immune regulation/inflammation. Given the pleiotropic effects of this cytokine, it comes as no surprise that numerous pathological conditions are associated with alterations in the TGF-β pathway, including chronic fibrosis, airway remodeling (asthma), cardiovascular disease and cancer. Thus, there are increasing efforts to develop reagents and therapeutic strategies to impair TGF-β signaling. Here we review several classes of inhibitors, including knockdown strategies aimed at signaling components of the TGF-β pathway, TGF-β neutralizing antibodies, TGF-β receptor extracellular domains that function as ligand traps and small molecule kinase inhibitors. Strategies with potential for application as anti-cancer therapeutics that have been evaluated in pre-clinical animal models will be discussed. TGF-β action is complex, shifting from a tumor suppressor to a promoter of tumor cell invasion and metastasis in several types of cancer. This raises important issues regarding not only the status of the TGF-β pathway in the individual patient but also the precise stage during disease progression that such inhibitors should be employed. Potential consequences of targeting the TGF-β pathway will also be considered.

Keywords: TGF-β Pathway, antagonists, ligand-traps, knock-down strategies, kinase inhibitors, targeted therapies, pre-clinical models, cancer