Death receptors as targets for anti-cancer therapy

Introduction Death receptor signalling TNF-R1 signalling CD95 signalling TRAIL-R signalling Targeting death receptors in cancer therapy Targeting TNF-R1 Isolated limb perfusion (ILP) Cell surface antigen-restricted activation of TNF-based fusion proteins Use of PEGylation to improve the specific anti-tumour effect of TNF Tumour targeted gene delivery of TNF Targeting CD95 Tissue-specific features of agonistic CD95 antibodies Cell surface antigen-restricted activation of CD95L-based fusion proteins CD95L-based gene therapy TRAIL as a target for anti-cancer therapy TRAIL-receptor agonists and their toxicities Responsiveness of primary tumour cells to TRAIL-mediated apoptosis Sensitization to TRAIL Clinical application of TRAIL-R agonists Future perspectives Human tumour cells are characterized by their ability to avoid the normal regulatory mechanisms of cell growth, division and death. The classical chemotherapy aims to kill tumour cells by causing DNA damage-induced apoptosis. However, as many tumour cells posses mutations in intracellular apoptosis-sensing molecules like p53, they are not capable of inducing apoptosis on their own and are therefore resistant to chemotherapy. With the discovery of the death receptors the opportunity arose to directly trigger apoptosis from the outside of tumour cells, thereby circumventing chemotherapeutic resistance. Death receptors belong to the tumour necrosis factor receptor superfamily, with tumour necrosis factor (TNF) receptor-1, CD95 and TNF-related apoptosis-inducing ligand-R1 and -R2 being the most prominent members. This review covers the current knowledge about these four death receptors, summarizes pre-clinical approaches engaging these death receptors in anti-cancer therapy and also gives an overview about their application in clinical trials conducted to date.