TRAIL on trial: preclinical advances in cancer therapy

Stuckey, Daniel W.; Shah, Khalid

doi:10.1016/j.molmed.2013.08.007

Cited by 254 publications

(213 citation statements)

References 79 publications

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“…In addition, as TRAIL does not only bind to DR4 and DR5, but also to decoy receptors DCR1, DCR2, and OPG (osteoprotegerin; ref. 39) in vivo tumor activity may be limited.…”

Section: Discussionmentioning

confidence: 99%

RG7386, a Novel Tetravalent FAP-DR5 Antibody, Effectively Triggers FAP-Dependent, Avidity-Driven DR5 Hyperclustering and Tumor Cell Apoptosis

Brünker

Wartha

Friess

et al. 2016

Molecular Cancer Therapeutics

103

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Dysregulated cellular apoptosis and resistance to cell death are hallmarks of neoplastic initiation and disease progression. Therefore, the development of agents that overcome apoptosis dysregulation in tumor cells is an attractive therapeutic approach. Activation of the extrinsic apoptotic pathway is strongly dependent on death receptor (DR) hyperclustering on the cell surface. However, strategies to activate DR5 or DR4 through agonistic antibodies have had only limited clinical success. To pursue an alternative approach for tumor-targeted induction of apoptosis, we engineered a bispecific antibody (BsAb), which simultaneously targets fibroblast-activation protein (FAP) on cancerassociated fibroblasts in tumor stroma and DR5 on tumor cells. We hypothesized that bivalent binding to both FAP and DR5 leads to avidity-driven hyperclustering of DR5 and subsequently strong induction of apoptosis in tumor cells but not in normal cells.Here, we show that RG7386, an optimized FAP-DR5 BsAb, triggers potent tumor cell apoptosis in vitro and in vivo in preclinical tumor models with FAP-positive stroma. RG7386 antitumor efficacy was strictly FAP dependent, was independent of FcR crosslinking, and was superior to conventional DR5 antibodies. In combination with irinotecan or doxorubicin, FAP-DR5 treatment resulted in substantial tumor regression in patient-derived xenograft models. FAP-DR5 also demonstrated single-agent activity against FAP-expressing malignant cells, due to cross-binding of FAP and DR5 across tumor cells. Taken together, these data demonstrate that RG7386, a novel and potent antitumor agent in both mono-and combination therapies, overcomes limitations of previous DR5 antibodies and represents a promising approach to conquer tumor-associated resistance to apoptosis.

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“…In addition, as TRAIL does not only bind to DR4 and DR5, but also to decoy receptors DCR1, DCR2, and OPG (osteoprotegerin; ref. 39) in vivo tumor activity may be limited.…”

Section: Discussionmentioning

confidence: 99%

RG7386, a Novel Tetravalent FAP-DR5 Antibody, Effectively Triggers FAP-Dependent, Avidity-Driven DR5 Hyperclustering and Tumor Cell Apoptosis

Brünker

Wartha

Friess

et al. 2016

Molecular Cancer Therapeutics

103

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“…It is particularly attractive as a cancer therapy since it is able to selectively trigger apoptosis in transformed cells, leaving healthy cells unharmed. TRAIL works through the extrinsic apoptosis pathway (see figure 1), however some cross-talk does occur with the intrinsic system that responds to cellular stress, p53 activation and DNA damage [5].…”

Section: Choosing An Anti-cancer Therapymentioning

confidence: 99%

“…Investigators have since altered TRAIL to improve its therapeutic performance through 'tagging' with another protein to increase its size, or using a PEGylated form with protracted half-life and efficacy [5]. Monoclonal antibodies (MAbs) to TRAIL receptors have also been investigated, however, the presence of TRAIL decoy receptors and recruitment of immune have again led to disappointing results.…”

Section: Choosing An Anti-cancer Therapymentioning

confidence: 99%

Combined cell-gene therapy for lung cancer: rationale, challenges and prospects

Thakrar

Sage

Janes

2016

Expert Opinion on Biological Therapy

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Lung cancer causes more deaths worldwide than any other cancer with most patients presenting with incurable metastatic disease. Mesenchymal stem cell tumour tropism presents us with an interesting mechanism of delivering potent therapies locally to cancers. Genetic modification of MSCs enables continued delivery of selective anticancer treatments such as TRAIL. While this is an attractive therapeutic option, translating such a therapy into patients presents challenges both in manufacture and delineation of dose and dosing strategy. However, successful delivery of a combined cell-gene therapy in lung cancer may offer promise to thousands of individuals largely resigned to poorly effective palliative treatments.

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“…The death-inducing signaling complex is activated by binding to its death receptors, DR4 and DR5, which then associates with the adaptor molecules FADD and caspase-8, resulting in the TRAIL-mediated activation of caspase-9 and subsequent activation of caspase-3 to induce apoptosis [5,6]. The release of cytochrome c and Smac/DIABLO from the mitochondria modulates caspase-3 activation and TRAIL via an intrinsic pathway when apoptosis is being induced [7].…”

Section: Introductionmentioning

confidence: 99%

Resveratrol Sensitizes Lung Cancer Cell to TRAIL by p53 Independent and Suppression of Akt/NF-κB Signaling

Rasheduzzaman

Jeong

Park

2018

Preprint

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Aims: TRAIL is a promising anticancer agent that has the potential to sensitize a wide variety of cancer or transformed cells by inducing apoptosis. However, resistance to TRAIL is a growing concern. Current manuscript aimed to employ combination treatment to investigate resveratrol induced TRAIL sensitization in NSCLC. Method: A549 and HCC-15 cells were used in an experimental design. Cell viability was determined by morphological image, crystal violet staining and MTT assay. Apoptosis was evaluated by LDH assay, Annexin V and DAPI staining. Autophagy and apoptosis indicator protein were examined by western blotting. TEM and puncta assay was carried out to evaluate the autophagy. MTP and ROS activity was evaluated by JC-1 and H 2 DCFDA staining. Findings: Resveratrol is a polyphenolic compound capable of activation of tumor suppressor p53 and its proapoptotic modulator PUMA. Herein, we showed the p53-independent apoptosis by decrease the expression of phosphorylated Akt-mediated suppression of NF-κB that is also substantiated with the downregulation of antiapoptotic factors Bcl-2 and Bcl-xl in NSCLC, resulting in an attenuation of TRAIL resistance in combined treatment. Furthermore, apoptosis was induced in TRAIL-resistant lung cancer cells with a co-treatment of resveratrol and TRAIL assessed by the loss of MMP, ROS generations which resulting the translocation of cytochrome c from the mitochondria into the cytosol due to mitochondrial dysfunction. Moreover, autophagy flux was not affected by resveratrol-induced TRAIL-mediated apoptosis in NSCLC. Significance: Overall, targeting the NF-κB (p65) pathway via resveratrol attenuates TRAIL resistance and induces TRAIL-mediated apoptosis which could be the effective TRAIL-based cancer therapy regimen.

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TRAIL on trial: preclinical advances in cancer therapy

Cited by 254 publications

References 79 publications

RG7386, a Novel Tetravalent FAP-DR5 Antibody, Effectively Triggers FAP-Dependent, Avidity-Driven DR5 Hyperclustering and Tumor Cell Apoptosis

RG7386, a Novel Tetravalent FAP-DR5 Antibody, Effectively Triggers FAP-Dependent, Avidity-Driven DR5 Hyperclustering and Tumor Cell Apoptosis

Combined cell-gene therapy for lung cancer: rationale, challenges and prospects

Resveratrol Sensitizes Lung Cancer Cell to TRAIL by p53 Independent and Suppression of Akt/NF-κB Signaling

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TRAIL on trial: preclinical advances in cancer therapy

Cited by 254 publications

References 79 publications

RG7386, a Novel Tetravalent FAP-DR5 Antibody, Effectively Triggers FAP-Dependent, Avidity-Driven DR5 Hyperclustering and Tumor Cell Apoptosis

RG7386, a Novel Tetravalent FAP-DR5 Antibody, Effectively Triggers FAP-Dependent, Avidity-Driven DR5 Hyperclustering and Tumor Cell Apoptosis

Combined cell-gene therapy for lung cancer: rationale, challenges and prospects

Resveratrol Sensitizes Lung Cancer Cell to TRAIL by p53 Independent and Suppression of Akt/NF-&kappa;B Signaling

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Resveratrol Sensitizes Lung Cancer Cell to TRAIL by p53 Independent and Suppression of Akt/NF-κB Signaling