The TRAIL in the Treatment of Human Cancer: An Update on Clinical Trials

Snajdauf, Martin; Havlová, K.; Vachtenheim, J; Ozaniak, Andrej; Lischke, Robert; Bartůňková, Jiřina; Smrž, Daniel; Střížová, Zuzana

doi:10.3389/fmolb.2021.628332

Cited by 84 publications

(68 citation statements)

References 58 publications

(64 reference statements)

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“…In phase I and also in phase II clinical trials, mapatumumab has demonstrated a remarkable safety profile and, resulted in complete or partial clinical responses when injected as monotherapy in patients suffering from follicular NHL ( 216 ). Mapatumumab was shown to be well tolerated up to 20 mg/kg daily and its potent therapeutic effects has been investigated for treatment of NSCLC, multiple myeloma, NHL, and HCC ( 216 , 217 ). Currently, a phase II multicenter study on 38 patients suffering from CRC verified the safety but not significant efficacy of the mapatumumab therapy ( 218 ).…”

Section: Trail-r Agonistic Monoclonal Antibodymentioning

confidence: 99%

“…Among the TRAIL-R2 agonistic antibodies, lexatumumab, drozitumab, DS-8273a, and LBY-135, have completed the phase I clinical trials. Further, tigatuzumab and conatumumab entered the phase II of clinical testing ( 217 ). Investigation of the possible anti-tumor effects of the agonistic antibody (DS-8273a) on 16 patients with advanced cancers evidenced that DS-8273a therapy resulted in the decrease of myeloid-derived suppressor cells (MDSC) in 50% of the patients, supporting DS-8273a utility in combination immunotherapy of cancer ( 221 ).…”

Section: Trail-r Agonistic Monoclonal Antibodymentioning

confidence: 99%

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RETRACTED: Harnessing TRAIL-Induced Apoptosis Pathway for Cancer Immunotherapy and Associated Challenges

et al. 2021

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The immune cytokine tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has attracted rapidly evolving attention as a cancer treatment modality because of its competence to selectively eliminate tumor cells without instigating toxicity in vivo. TRAIL has revealed encouraging promise in preclinical reports in animal models as a cancer treatment option; however, the foremost constraint of the TRAIL therapy is the advancement of TRAIL resistance through a myriad of mechanisms in tumor cells. Investigations have documented that improvement of the expression of anti-apoptotic proteins and survival or proliferation involved signaling pathways concurrently suppressing the expression of pro-apoptotic proteins along with down-regulation of expression of TRAILR1 and TRAILR2, also known as death receptor 4 and 5 (DR4/5) are reliable for tumor cells resistance to TRAIL. Therefore, it seems that the development of a therapeutic approach for overcoming TRAIL resistance is of paramount importance. Studies currently have shown that combined treatment with anti-tumor agents, ranging from synthetic agents to natural products, and TRAIL could result in induction of apoptosis in TRAIL-resistant cells. Also, human mesenchymal stem/stromal cells (MSCs) engineered to generate and deliver TRAIL can provide both targeted and continued delivery of this apoptosis-inducing cytokine. Similarly, nanoparticle (NPs)-based TRAIL delivery offers novel platforms to defeat barricades to TRAIL therapeutic delivery. In the current review, we will focus on underlying mechanisms contributed to inducing resistance to TRAIL in tumor cells, and also discuss recent findings concerning the therapeutic efficacy of combined treatment of TRAIL with other antitumor compounds, and also TRAIL-delivery using human MSCs and NPs to overcome tumor cells resistance to TRAIL.

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Section: Trail-r Agonistic Monoclonal Antibodymentioning

confidence: 99%

Section: Trail-r Agonistic Monoclonal Antibodymentioning

confidence: 99%

RETRACTED: Harnessing TRAIL-Induced Apoptosis Pathway for Cancer Immunotherapy and Associated Challenges

et al. 2021

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“…Activation of extrinsic apoptotic signaling by TRAIL receptor agonists provoked mutations in surviving cells [ 161 , 162 ], and the minority MOMP and subsequent caspase-mediated mutagenesis provoked by BH3-mimetic drugs facilitated oncogenic transformation in vivo [ 168 ]. TRAIL receptor agonists have not yet been approved for clinical use [ 309 ], and the clinical use of such BH3 mimetics are still in relatively early stages, so the frequency of subsequent cancers in patients treated with these agents will not be evident for many years.…”

Section: Discussionmentioning

confidence: 99%

Mutagenic Consequences of Sublethal Cell Death Signaling

Hawkins

Miles

2021

IJMS

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Many human cancers exhibit defects in key DNA damage response elements that can render tumors insensitive to the cell death-promoting properties of DNA-damaging therapies. Using agents that directly induce apoptosis by targeting apoptotic components, rather than relying on DNA damage to indirectly stimulate apoptosis of cancer cells, may overcome classical blocks exploited by cancer cells to evade apoptotic cell death. However, there is increasing evidence that cells surviving sublethal exposure to classical apoptotic signaling may recover with newly acquired genomic changes which may have oncogenic potential, and so could theoretically spur the development of subsequent cancers in cured patients. Encouragingly, cells surviving sublethal necroptotic signaling did not acquire mutations, suggesting that necroptosis-inducing anti-cancer drugs may be less likely to trigger therapy-related cancers. We are yet to develop effective direct inducers of other cell death pathways, and as such, data regarding the consequences of cells surviving sublethal stimulation of those pathways are still emerging. This review details the currently known mutagenic consequences of cells surviving different cell death signaling pathways, with implications for potential oncogenic transformation. Understanding the mechanisms of mutagenesis associated (or not) with various cell death pathways will guide us in the development of future therapeutics to minimize therapy-related side effects associated with DNA damage.

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“…Overcoming TRAIL resistance in melanoma may potentiate the tumoricidal action of the immune system and virtually act in concert with checkpoint inhibitor-targeted immunotherapy. It is noticeable that deregulation of TRAIL-R intracellular signaling, primarily due to aberrant NF-κB activation, often deviates signal from cell death to cell survival ( Snajdauf et al, 2021 ). The well-known FKBP51 role in supporting NF-κB activation ( Romano et al, 2015 ) makes this immunophilin an ideal target to restore TRAIL sensitivity of melanoma.…”

Section: Discussionmentioning

confidence: 99%

FKBP51 Affects TNF-Related Apoptosis Inducing Ligand Response in Melanoma

Tufano

Cesaro

Martinelli

et al. 2021

Front. Cell Dev. Biol.

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Melanoma is one of the most immunogenic tumors and has the highest potential to elicit specific adaptive antitumor immune responses. Immune cells induce apoptosis of cancer cells either by soluble factors or by triggering cell-death pathways. Melanoma cells exploit multiple mechanisms to escape immune system tumoricidal control. FKBP51 is a relevant pro-oncogenic factor of melanoma cells supporting NF-κB-mediated resistance and cancer stemness/invasion epigenetic programs. Herein, we show that FKBP51-silencing increases TNF-related apoptosis-inducing ligand (TRAIL)-R2 (DR5) expression and sensitizes melanoma cells to TRAIL-induced apoptosis. Consistent with the general increase in histone deacetylases, as by the proteomic profile, the immune precipitation assay showed decreased acetyl-Yin Yang 1 (YY1) after FKBP51 depletion, suggesting an impaired repressor activity of this transcription factor. ChIP assay supported this hypothesis. Compared with non-silenced cells, a reduced acetyl-YY1 was found on the DR5 promoter, resulting in increased DR5 transcript levels. Using Crispr/Cas9 knockout (KO) melanoma cells, we confirmed the negative regulation of DR5 by FKBP51. We also show that KO cells displayed reduced levels of acetyl-EP300 responsible for YY1 acetylation, along with reduced acetyl-YY1. Reconstituting FKBP51 levels contrasted the effects of KO on DR5, acetyl-YY1, and acetyl-EP300 levels. In conclusion, our finding shows that FKBP51 reduces DR5 expression at the transcriptional level by promoting YY1 repressor activity. Our study supports the conclusion that targeting FKBP51 increases the expression level of DR5 and sensitivity to TRAIL-induced cell death, which can improve the tumoricidal action of immune cells.

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The TRAIL in the Treatment of Human Cancer: An Update on Clinical Trials

Cited by 84 publications

References 58 publications

RETRACTED: Harnessing TRAIL-Induced Apoptosis Pathway for Cancer Immunotherapy and Associated Challenges

RETRACTED: Harnessing TRAIL-Induced Apoptosis Pathway for Cancer Immunotherapy and Associated Challenges

Mutagenic Consequences of Sublethal Cell Death Signaling

FKBP51 Affects TNF-Related Apoptosis Inducing Ligand Response in Melanoma

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