Potent Systemic Anticancer Activity of Adenovirally Expressed EGFR-Selective TRAIL Fusion Protein

Bremer, Edwin; Dam, Gooitzen M. van; Bruyn, Marco de; Riezen, Manon van; Dijkstra, Marike H.; Kamps, Gera; Helfrich, Wijnand; Haisma, Hidde J.

doi:10.1038/mt.2008.203

Cited by 30 publications

(27 citation statements)

References 29 publications

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“…Previously, we generated proof of concept data for such dual therapeutic signaling with scFv:TRAIL fusion proteins, using an scFv:TRAIL fusion protein that targeted the Epidermal Growth Factor Receptor [16,19]. Here, the EGFR-inhibitory antibody fragment blocked mitogenic EGFR-signaling and synergized TRAIL apoptotic signaling [16,19].…”

Section: Resultsmentioning

confidence: 99%

Melanoma-associated Chondroitin Sulfate Proteoglycan (MCSP)-targeted delivery of soluble TRAIL potently inhibits melanoma outgrowth in vitro and in vivo

et al. 2010

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BackgroundAdvanced melanoma is characterized by a pronounced resistance to therapy leading to a limited patient survival of ~6 - 9 months. Here, we report on a novel bifunctional therapeutic fusion protein, designated anti-MCSP:TRAIL, that is comprised of a melanoma-associated chondroitin sulfate proteoglycan (MCSP)-specific antibody fragment (scFv) fused to soluble human TRAIL. MCSP is a well-established target for melanoma immunotherapy and has recently been shown to provide important tumorigenic signals to melanoma cells. TRAIL is a highly promising tumoricidal cytokine with no or minimal toxicity towards normal cells. Anti-MCSP:TRAIL was designed to 1. selectively accrete at the cell surface of MCSP-positive melanoma cells and inhibit MCSP tumorigenic signaling and 2. activate apoptotic TRAIL-signaling.ResultsTreatment of a panel of MCSP-positive melanoma cell lines with anti-MCSP:TRAIL induced TRAIL-mediated apoptotic cell death within 16 h. Of note, treatment with anti-MCSP:sTRAIL was also characterized by a rapid dephosphorylation of key proteins, such as FAK, implicated in MCSP-mediated malignant behavior. Importantly, anti-MCSP:TRAIL treatment already inhibited anchorage-independent growth by 50% at low picomolar concentrations, whereas > 100 fold higher concentrations of non-targeted TRAIL failed to reduce colony formation. Daily i.v. treatment with a low dose of anti-MCSP:TRAIL (0.14 mg/kg) resulted in a significant growth retardation of established A375 M xenografts. Anti-MCSP:TRAIL activity was further synergized by co-treatment with rimcazole, a σ-ligand currently in clinical trials for the treatment of various cancers.ConclusionsAnti-MCSP:TRAIL has promising pre-clinical anti-melanoma activity that appears to result from combined inhibition of tumorigenic MCSP-signaling and concordant activation of TRAIL-apoptotic signaling. Anti-MCSP:TRAIL alone, or in combination with rimcazole, may be of potential value for the treatment of malignant melanoma.

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Section: Resultsmentioning

confidence: 99%

Melanoma-associated Chondroitin Sulfate Proteoglycan (MCSP)-targeted delivery of soluble TRAIL potently inhibits melanoma outgrowth in vitro and in vivo

et al. 2010

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“…14 Recently, tumor-cell selective modification of soluble TRAIL by fusing epidermal growth factor receptordirected antibody (scFv425) showed a more selective and potent antitumor effect, 24 and a recombinant adenovirus that can express fusion protein (scFv425-TRAIL) demonstrated its clinical significance. 25 However, resistance to TRAIL prevents its clinical use and requires the combination with other chemicals. Combination of TRAIL and HDAC inhibitors are an attractive trial, because some properties of HDAC inhibitors can ameliorate the mechanisms of TRAIL resistance.…”

Section: Discussionmentioning

confidence: 99%

Combination of vorinostat and adenovirus-TRAIL exhibits a synergistic antitumor effect by increasing transduction and transcription of TRAIL in lung cancer cells

Park

et al. 2011

Cancer Gene Ther

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Soluble TRAIL and adenovirus (ad)-TRAIL exhibit a strong antitumor effect by inducing apoptosis. Vorinostat is the histone deacetylase (HDAC) inhibitor that induces cell death in cancer cell lines and regulates the expression of epigenetically silenced genes, such as Coxackie adenoviral receptor (CAR), the receptor for adenoviral entry. We propose a new strategy in which vorinostat will induce high expression of ad-TRAIL and a strong antitumor response, and investigated the mechanism involved. The effect of vorinostat on transcription and expression of TRAIL from ad-TRAIL-transduced lung cancer cells were confirmed by reverse transciption-PCR (RT-PCR), quantitative real time-PCR and western blot assay. Anti-tumor effects were measured after cotreatment of vorinostat and ad-TRAIL, and the drug interactions were analyzed. After combined treatment of vorinostat and ad-TRAIL, apoptosis and western blot assays for Akt, Bcl-2 and caspase were performed. Vorinostat increased the expression of CAR in lung cancer cell lines and increased the expression of luciferase (luc) from ad-luc-transduced cells and TRAIL from ad-TRAIL-transduced cells. RT-PCR and quantitative real time-PCR, after sequential vorinostat treatment, revealed that vorinostat may enhance TRAIL expression from ad-TRAIL by increasing transduction through enhanced CAR expression and increasing adenoviral transgene transcription. Combined vorinostat and ad-TRAIL treatment showed the synergistic anti-tumor effect in lung cancer cell lines. Combined vorinostat and ad-TRAIL induced stronger apoptosis induction, suppression of NF-kB activation and breakdown of the anti-apoptotic molecule Bcl-2. In conclusion, the vorinostat synergistically enhanced the anti-tumor effect of ad-TRAIL by (1) increasing adenoviral transduction through the increased expression of CAR and (2) increasing adenoviral transgene (TRAIL) transcription in lung cancer cell lines.

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“…Since our initial report, there have been a number of recombinant viral vectors containing the TRAIL cDNA described in the literature (Armeanu et al, 2003; Carlo-Stella et al, 2006; Dong et al, 2006; Griffith and Broghammer, 2001; Kagawa et al, 2001; Kock et al, 2007; Lee et al, 2002; Lillehammer et al, 2007; Seol et al, 2003; Voelkel-Johnson et al, 2002; Wenger et al, 2007; Yang et al, 2006; Zhang et al, 2008). Most recently, a recombinant fusion protein consisting of an endothelial growth factor receptor (EGFR)-directed antibody fragment fused to soluble TRAIL has been delivered via a replication-deficient adenovirus (Bremer et al, 2008). Mice with established intraperitoneal renal cell carcinoma xenografts that received a single intraocular injection of the virus experienced significant tumor load reduction and increased survival with no signs of hepatic toxicity despite predominant infection of the liver.…”

Section: Preclinical Studiesmentioning

confidence: 99%

TNF-related apoptosis-inducing ligand (TRAIL): A new path to anti-cancer therapies

Holoch

Griffith

2009

European Journal of Pharmacology

161

159

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Since its discovery in 1995, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor super family, has been under intense focus because of its remarkable ability to induce apoptosis in malignant human cells while leaving normal cells unscathed. Consequently, activation of the apoptotic signaling pathway from the death-inducing TRAIL receptors provides an attractive, biologically-targeted approach to cancer therapy. A great deal of research has focused on deciphering the TRAIL receptor signaling cascade and intracellular regulation of this pathway, as many human tumor cells possess mechanisms of resistance to TRAILinduced apoptosis. This review focuses on the currently state of knowledge regarding TRAIL signaling and resistance, the preclinical development of therapies targeted at TRAIL receptors and modulators of the pathway, and the results of clinical trials for cancer treatment that have emerged from this base of knowledge. TRAIL-based approaches to cancer therapy vary from systemic administration of recombinant, soluble TRAIL protein with or without the combination of traditional chemotherapy, radiation or novel anticancer agents to agonistic monoclonal antibodies directed against functional TRAIL receptors to TRAIL gene transfer therapy. A better understanding of TRAIL resistance mechanisms may allow for the development of more effective therapies that exploit this cell-mediated pathway to apoptosis.

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Potent Systemic Anticancer Activity of Adenovirally Expressed EGFR-Selective TRAIL Fusion Protein

Cited by 30 publications

References 29 publications

Melanoma-associated Chondroitin Sulfate Proteoglycan (MCSP)-targeted delivery of soluble TRAIL potently inhibits melanoma outgrowth in vitro and in vivo

Melanoma-associated Chondroitin Sulfate Proteoglycan (MCSP)-targeted delivery of soluble TRAIL potently inhibits melanoma outgrowth in vitro and in vivo

Combination of vorinostat and adenovirus-TRAIL exhibits a synergistic antitumor effect by increasing transduction and transcription of TRAIL in lung cancer cells

TNF-related apoptosis-inducing ligand (TRAIL): A new path to anti-cancer therapies

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