Tumor necrosis factor: renaissance as a cancer therapeutic?
Since the discovery of tumor necrosis factor (TNF)-alpha, researchers have pursued many approaches to harness the potency of TNF-alpha and TNF superfamily members to treat human cancers. Several ligands of the TNF superfamily, including TNF-alpha, lymphotoxin, FAS ligand (FasL), and APO2 ligand/TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) have been tested in various stages of clinical research for their anti-tumor efficacy. Moreover, several antibodies to TNF receptor (TNFR) superfamily members are now being explored as cancer therapeutics. Due to the toxicity associated with delivering TNF-alpha systemically at clinically relevant doses, more targeted methods are now seen as a likely alternative to provide a localized therapeutically effective dose of TNF-alpha. In this review we revisit historical attempts to use TNF-alpha to treat human cancer, and put this into the context of more recent targeted strategies to circumvent TNF-alpha's systemic toxicity. We will attempt to integrate the results of pre-clinical and clinical trials with a concise synopsis of the TNF-alpha signaling network, with the goal of reconciling our understanding of how the cell biology and tumor biology mechanistically relate.
Daniel
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Department of Molecular Oncology, Genentech, Inc., South San Francisco, CA 94080, USA. ddaniel@gene.com
Wilson
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D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000627:therapeutic use*; D002986:Clinical Trials as Topic / Q000379:methods; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors