Mini-reviewTRAIL and cancer therapy
Section snippets
TRAIL and its receptors
More than a decade ago, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, Apo2L, TNFSF10) was identified as a powerful activator of programmed cell death or apoptosis in tumor cells while sparing normal cells [1], [2]. This feature has greatly spurred research to explore the potential of TRAIL as an anticancer therapy and to the mechanisms underlying its antitumor properties.
TRAIL belongs to the tumor necrosis factor (TNF) superfamily that includes cytokines such as TNF and FasL
TRAIL in apoptosis signaling
The mechanisms underlying apoptosis activation by TRAIL have been studied in most detail. After binding of TRAIL to TRAIL-R1 or -R2 the trimerized receptors recruit several cytosolic proteins that form the death-inducing signaling complex (DISC) (see also Fig. 1). FADD (Fas-associated protein with death domain) is an adaptor protein that binds directly to the intracellular death domain of the receptors where it simultaneously binds the inactive pro-form of caspase-8 or caspase-10 via a shared
TRAIL in non-apoptotic signaling
TNF receptor family members can apart from apoptosis activation induce to varying extents signaling pathways for inflammation, differentiation and cell survival [17]. Although TRAIL has strong apoptosis activation properties in most susceptible cells, evidence is accumulating for its ability to activate prosurvival and proliferation signaling mediated by NF-κB, JNK and p38 mitogen-activated protein kinase (MAPK) pathways (for review see Ref. [5]). Molecular determinants of kinase activation by
Regulation of TRAIL signaling
TRAIL signaling is regulated at different levels throughout the pathway, from receptors to downstream caspases. At the receptor level the decoy receptors have been proposed to act as competitors for TRAIL binding to DR4 and DR5 [4], [21], although DcR1 and DcR2 act in different ways. DcR1 acts as a simple competitor, whereas DcR2-mediated inhibition involves the formation of heterologous complexes with DR5, acting more like a “regulatory” than “decoy” receptor [22]. The function of soluble OPG
TRAIL receptor targeting agents
The selective killing of tumor cells by TRAIL has made TRAIL receptors attractive targets for cancer treatment. The cellular and molecular basis for this selectivity is not completely understood. It could be related to the higher expression of the TRAIL-receptors in tumor cells, or to the relative high level of decoy receptors in normal cells [35], but may also involve non-functionality of the pathway at more downstream levels. In this context, it could be proposed that oncogenic activation
TRAIL resistance and strategies for sensitization
TRAIL resistance has been reported in approximately 50% of tested tumor cell lines thus tempering the expectations of monotherapy in the clinic [4]. In a number of tumors, including breast and lung cancer, resistance to TRAIL has been correlated with mutations in TRAIL-R1 and TRAIL-R2 in approximately 10% of the tumors examined [51], [52]. Although these mutations may cause a structural failure in TRAIL signaling in a small percentage of tumors, genetic aberrations were found in only one TRAIL
TRAIL in combination with other targeted agents
The increasing knowledge of the TRAIL signaling pathway has lead to the rationalized use of specific agents directed against potential apoptotic blockades in the pathway or agents that suppress the prosurvival signaling abilities of TRAIL. Below several examples are given for these TRAIL sensitizing strategies. Targeting of antiapoptotic Bcl-2 family members in combination with TRAIL-based therapy has been tested in different tumor cell types. The small molecule Bcl-2 inhibitor HA14-1 [64] was
TRAIL therapy in the clinic
As illustrated above in preclinical models TRAIL therapy holds great promise for the treatment of cancer. However, the proof of the pudding is in the eating, and results of clinical studies have been eagerly awaited. Recently the first reports have appeared in the public domain.
Apo2/TRAIL (Genentech, South San Francisco, CA; Amgen, Thousand Oaks, CA) is currently evaluated in phase I trails. A preliminary report on this study in which fifty-one patients were enrolled and treated with escalating
Conclusions and future perspectives
TRAIL therapy holds promise as a novel selective antitumor therapy, which is supported by early results obtained in clinical studies in a range of advanced cancers of hematological and solid tumor origin revealing mild toxicities and evidence of beneficial therapeutic effects. Whether recombinant TRAIL or TRAIL receptor agonistic monoclonal antibodies will be most effective remains to be demonstrated in ongoing clinical studies and follow-ups. Both approaches have advantages and disadvantages,
Acknowledgements
Research in the laboratory of FAEK is funded by the Dutch Cancer Society KWF-NK Grant 2006-3567 and within the framework of Project T3-112 of the Dutch Top Institute Pharma. I thank Dr. Henk Broxterman for carefully reading the manuscript.
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