TRAIL therapy and prospective developments for cancer treatment

Abstract

Tumor Necrosis Factor (TNF) Related Apoptosis-Inducing Ligand (TRAIL), an immune cytokine of TNF-family, has received much attention in late 1990s as a potential cancer therapeutics due to its selective ability to induce apoptosis in cancer cells. TRAIL binds to cell surface death receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5) and facilitates formation of death-inducing signaling complex (DISC), eventually activating the p53-independent apoptotic cascade. This unique mechanism makes the TRAIL a potential anticancer therapeutic especially for p53-mutated tumors. However, recombinant human TRAIL protein (rhTRAIL) and TRAIL-R agonist monoclonal antibodies (mAb) failed to exert robust anticancer activities due to inherent and/or acquired resistance, poor pharmacokinetics and weak potencies for apoptosis induction. To get TRAIL back on track as a cancer therapeutic, multiple strategies including protein modification, combinatorial approach and TRAIL gene therapy are being extensively explored. These strategies aim to enhance the half-life and bioavailability of TRAIL and synergize with TRAIL action ultimately sensitizing the resistant and non-responsive cells. We summarize emerging strategies for enhanced TRAIL therapy in this review and cover a wide range of recent technologies that will provide impetus to rejuvenate the TRAIL therapeutics in the clinical realm.

Introduction

Majority of anticancer drugs are expected to inhibit uncontrolled cell proliferation and induce apoptosis. Among the apoptosis pathways, intrinsic or mitochondrial pathway is activated in response to cellular stress and DNA damage by chemotherapy and/or radiotherapy, and involves activation of p53 and release of pro-apoptotic factors from the mitochondria [1,2]. Conventional chemotherapy, however, generally lacks cell selectivity and, moreover, majority of tumors involves mutation(s) of p53 that impede the activation of innate apoptosis mechanism. Alternatively, Tumor Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL, also known as Apo2L), a member of the Tumor Necrosis Factor (TNF) superfamily, induces extrinsic apoptotic pathway, where p53 appears to be dispensable, to induce apoptosis in p53-mutated cancers. TRAIL is a cytokine secreted by majority of normal cells as a part of natural immune reaction and play a significant role in preventing cell proliferation [3]. TRAIL quickly emerged as a promising cancer therapeutic after its discovery because of its ability to induce apoptosis in a wide range of cancer cells while sparing the normal cells [4,5]. Increased interest in TRAIL therapy led to development of recombinant human TRAIL (rhTRAIL) proteins and TRAIL receptor (TRAIL-R1 and TRAIL-R2) agonist monoclonal antibodies (mAb) as potential cancer therapeutics. The promising preclinical results propelled the TRAIL therapy to several clinical trails to test its safety, pharmacokinetics and efficacy in cancer [6,7]. Most studies showed that TRAIL therapy was safe and well-tolerated in patients, but the therapeutic outcomes were insignificant, only a small population of patients showing an effective response [1,[6], [7], [8], [9]].

The recent interest in TRAIL-based intervention led to development of multiple approaches, including TRAIL conjugates, combinatorial approaches, TRAIL gene therapy, and cell-based therapy (Fig. 1). Numerous studies have explored these approaches in both in vitro and in vivo models with many promising outcomes. The objective of this review is to highlight the opportunities and challenges for improving TRAIL-based cancer therapy. We first start with the mechanism of action for TRAIL protein and catalogue various approaches to enhance TRAIL therapy based on this mechanistic insight. We focussed on TRAIL protein based and expression systems for intervention and avoided modified cell-based delivery approaches. We note that engineered MSCs, as well as other types of cells, could show effective migration to sites of action for improved concentration of TRAIL [10,11]. Adipose tissue derived MSCs [12], bone marrow derived MSCs [13], human umbilical cord MSCs (HUMSC) [14] for TRAIL delivery, as well as several non-viral approaches to engineer human stem cells to secrete TRAIL [[15], [16], [17], [18]]. We refer the reader to the above studies on cell-based TRAIL delivery approaches. We also note that others have reviewed TRAIL therapy elsewhere [7,10,19,20], and we refer the reader for a different perspective on the topic.