Therapeutic targeting of the TNF superfamily: A promising treatment for advanced endometrial adenocarcinoma

Surgical treatment including total abdominal hysterectomy + bilateral salpingo oopherectomy (TAH + BSO) with pelvic and para-aortic lymphadenectomy may not be sufficient to treat cases with advanced endometrial adenocarcinoma (EAC), and in these cases, adjuvant treatments including radiotherapy and/or chemotherapy, are employed based upon the tumor location, type and stage of the disease. These treatment modalities have high incidence of systemic toxicity, thereby compelling clinicians to look for targeted therapy aiming specifically at the malignant cells. Bevacizumab (anti-VEGF), temsirolimus (mTOR inhibitor) and aflibercept (VEGF trap) are already under clinical trials in women with EAC. Targeting the ligands and receptors of the tumor necrosis factor (TNF) superfamily holds promise in this regard. The objective of this review is to provide an overview of the various mechanisms and pathways related to the TNF superfamily involved in advanced EAC and to identify the new therapeutic strategies for specifically targeting these impaired pathways. In addition, the development of treatments for EAC is also discussed. The possible therapeutic treatments include targeting TNF alpha and its receptors using monoclonal antibodies (MAbs) such as infliximab, adalimumab, etanercept, and certolizumab. Proteosome inhibitors including bortezomib and the anti CD-20 agent rituximab are used to inhibit the NF-kappa B pathway. Other options include targeting the FAS (CD95) pathway and the TNF-related apoptosis-inducing ligand (TRAIL) pathway using agents such as mapatumab, lexatumumab, and conatumumab. These pathways are known to be involved in the pathogenesis of EAC. Moreover, there is adequate evidence to warrant the use of drugs that target the TNF superfamily for the treatment of advanced EAC. (c) 2012 Elsevier Inc. All rights reserved.