Opportunities and challenges in combination gene cancer therapy

Abstract

Treatment for solid tumor malignancies, which constitute the majority of human cancers, is still dominated by surgery and radiotherapies. This is especially true for many localized solid tumors, which are often curable with these treatments. However, metastatic cancers are beyond the reach of these therapies, and many localized cancers that are initially treated with surgery and radiation will recur and metastasize. Thus, for over 60years there has been a concerted effort to develop effective drug treatments for metastatic cancers. Combination therapies are an increasingly important part of the anti-cancer drug armamentarium. In the case of cytotoxic chemotherapy, multi-drug regimens rapidly became the norm, as the earliest single agents were relatively ineffective. In contrast to chemotherapy, where combination therapies were required in order to achieve treatment efficacy, for both hormonal and targeted therapies the impetus to move toward the use of combination therapies is to prevent or reverse the development of treatment resistance. In addition, emerging evidence suggests that combination therapy may also improve cancer treatment by neutralizing an emerging treatment side effect termed therapy-induced metastasis, which accompanies some effective single agent therapies. Finally, although gene therapy is still far from use in the clinic, we propose that combination therapies may enhance its effectiveness.

Keywords: Cancer; Chemotherapy; Death receptors; Gene therapy; Hormonal therapy; Targeted therapy; Therapeutics; c-FLIP.

Figure 1. TNF signaling network

TNF can signal either survival or apoptosis via its receptor, TNFR1. NFκB and the caspase-8 inhibitor c-FLIP (FLIP) are key intracellular regulators that control the switch between apoptosis and survival signaling.