Abstract
TRAIL (tumor-necrosis factor related apoptosis-inducing ligand, CD253) and its death receptors TRAIL-R1 and TRAIL-R2 selectively trigger the apoptotic cell death in tumor cells. For that reason, TRAIL has been extensively studied as a target of cancer therapy. In spite of the promising preclinical observations, the TRAIL–based therapies in humans have certain limitations. The two main therapeutic approaches are based on either an administration of TRAIL-receptor (TRAIL-R) agonists or a recombinant TRAIL. These approaches, however, seem to elicit a limited therapeutic efficacy, and only a few drugs have entered the phase II clinical trials. To deliver TRAIL-based therapies with higher anti-tumor potential several novel TRAIL-derivates and modifications have been designed. These novel drugs are, however, mostly preclinical, and many problems continue to be unraveled. We have reviewed the current status of all TRAIL-based monotherapies and combination therapies that have reached phase II and phase III clinical trials in humans. We have also aimed to introduce all novel approaches of TRAIL utilization in cancer treatment and discussed the most promising drugs which are likely to enter clinical trials in humans. To date, different strategies were introduced in order to activate anti-tumor immune responses with the aim of achieving the highest efficacy and minimal toxicity.In this review, we discuss the most promising TRAIL-based clinical trials and their therapeutic strategies.
Highlights
Several therapeutic strategies are currently subjected to testing with the aim to trigger the antitumor immune responses (Zhang and Zhang, 2020; Nagai and Kim, 2017)
The mechanism of action of recombinant soluble TRAIL protein is based on its binding to TRAIL-R1 and TRAIL-R2 leading to subsequent activation of caspases and the apoptotic cell death (Zhang et al, 2010)
The mechanism underlying the selective induction of apoptosis in tumor cells has not yet been elucidated, even though the significantly higher expression of TRAIL’s decoy receptors in non-malignant cells may provide some answers (Micheau et al, 2013)
Summary
Several therapeutic strategies are currently subjected to testing with the aim to trigger the antitumor immune responses (Zhang and Zhang, 2020; Nagai and Kim, 2017). TRAIL (tumor—necrosis factor related apoptosis-inducing ligand, CD253) is a protein initially described to selectively trigger extrinsic apoptotic pathway in malignant cells (Micheau et al, 2013). The binding of TRAIL to its death receptors, DR4 and DR5, causes a homotypic DD–dependent recruitment of Fas-associated protein with death domain (FADD). Since the apoptosis mediated by TRAIL is known to trigger the extrinsic signaling pathway, its combination with conventional chemotherapeutic drugs seems relevant as they engage the intrinsic (mitochondrial) apoptotic pathway, Figure 1. Inhibitory protein], Bcl-2 (B-cell lymphoma 2), or DcR1/DcR2 can restrain the caspase activation and lead to the TRAILmediated apoptosis resistance, Figure 1 (Dubuisson and Micheau, 2017). The mTRAIL and sTRAIL have been reported to recruit multiple procaspase molecules leading to the tumor cell death in vitro and in vivo (Ehrlich et al, 2003). The activation of NF-κB signaling pathway by KRAS was found to interfere with
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