A Single-Agent Dual-Specificity Targeting of FOLR1 and DR5 as an Effective Strategy for Ovarian Cancer

Shivange, Gururaj; Urbanek, Karol; Przanowski, Piotr; Perry, Justin C.; Jones, James O.; Haggart, Robert; Kostka, Christina; Patki, Tejal; Stelow, Edward B.; Petrova, Yuliya; Llaneza, Danielle C.; Mayo, Marty W.; Ravichandran, Kodi S.; Landen, Charles N.; Bhatnagar, Sanchita; Tushir-Singh, Jogender

doi:10.1016/j.ccell.2018.07.005

Cited by 29 publications

(101 citation statements)

References 49 publications

(83 reference statements)

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“…Targeted treatments and immunohistochemistry offer the hope of improved treatments for OC patients in the future. Moreover, identifying biomarkers for targeted treatments is important for effective cancer diagnosis and treatment ( Shivange et al, 2018 ; Villar-Prados et al, 2018 ). RNA sequencing is an accurate method used to identify such biomarkers ( Coenen-Stass et al, 2018 ; Jiang et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

“…The targeted treatment of OC plays an increasingly important role in the comprehensive treatment of OC and new tumor treatment strategies depend on the search for new targets ( Huang et al, 2018 ; Shivange et al, 2018 ; Villar-Prados et al, 2018 ; Zhai et al, 2018 ). With the development of sequencing technology and acquirement of a large amount of biological data, bioinformatics can be used to understand and find new biomarkers of tumor ( Yang et al, 2020 ; Wu et al, 2019 ; Tao et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of FGFR1 as a diagnostic biomarker for ovarian cancer using TCGA and GEO datasets

Xiao

Wang

et al. 2021

PeerJ

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Background Malignant ovarian cancer is associated with the highest mortality of all gynecological tumors. Designing therapeutic targets that are specific to OC tissue is important for optimizing OC therapies. This study aims to identify different expression patterns of genes related to FGFR1 and the usefulness of FGFR1 as diagnostic biomarker for OC. Methods We collected data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. In the TCGA cohort we analyzed clinical information according to patient characteristics, including age, stage, grade, longest dimension of the tumor and the presence of a residual tumor. GEO data served as a validation set. We obtained data on differentially expressed genes (DEGs) from the two microarray datasets. We then used gene set enrichment analysis (GSEA) to analyze the DEG data in order to identify enriched pathways related to FGFR1. Results Differential expression analysis revealed that FGFR1 was significantly downregulated in OC specimens. 303 patients were included in the TCGA cohort. The GEO dataset confirmed these findings using information on 75 Asian patients. The GSE105437 and GSE12470 database highlighted the significant diagnostic value of FGFR1 in identifying OC (AUC = 1, p = 0.0009 and AUC = 0.8256, p = 0.0015 respectively). Conclusions Our study examined existing TCGA and GEO datasets for novel factors associated with OC and identified FGFR1 as a potential diagnostic factor. Further investigation is warranted to characterize the role played by FGFR1 in OC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Evaluation of FGFR1 as a diagnostic biomarker for ovarian cancer using TCGA and GEO datasets

Xiao

Wang

et al. 2021

PeerJ

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“…This seems to be indeed the case. Plasma membrane binding-dependent agonism has, for example, been demonstrated by different groups for anti-TRAILR2 antibody fusion proteins with the ability to anchor to the plasma membrane with the help of a second antibody domain recognizing the cell surface antigens FAP, MCSP, and FolR1 ( Brunker et al, 2016 ; He et al, 2016 ; Shivange et al, 2018 ). Similarly, a 50- to >1,000-fold plasma membrane anchoring-dependent increase in their TNFR-stimulating potential has also been reported for various antibody fusion proteins targeting the category II TNFRs 4-1BB, CD27, CD40, CD95, Fn14, and TNFR2 ( Medler et al, 2019 ; Nelke et al, 2020 ).…”

Section: Tnf Receptor Activation Requirements: Consequences For the Dmentioning

confidence: 99%

Receptor Oligomerization and Its Relevance for Signaling by Receptors of the Tumor Necrosis Factor Receptor Superfamily

Kucka

Wajant

2021

Front. Cell Dev. Biol.

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With the exception of a few signaling incompetent decoy receptors, the receptors of the tumor necrosis factor receptor superfamily (TNFRSF) are signaling competent and engage in signaling pathways resulting in inflammation, proliferation, differentiation, and cell migration and also in cell death induction. TNFRSF receptors (TNFRs) become activated by ligands of the TNF superfamily (TNFSF). TNFSF ligands (TNFLs) occur as trimeric type II transmembrane proteins but often also as soluble ligand trimers released from the membrane-bound form by proteolysis. The signaling competent TNFRs are efficiently activated by the membrane-bound TNFLs. The latter recruit three TNFR molecules, but there is growing evidence that this is not sufficient to trigger all aspects of TNFR signaling; rather, the formed trimeric TNFL–TNFR complexes have to cluster secondarily in the cell-to-cell contact zone for full TNFR activation. With respect to their response to soluble ligand trimers, the signaling competent TNFRs can be subdivided into two groups. TNFRs of one group, designated as category I TNFRs, are robustly activated by soluble ligand trimers. The receptors of a second group (category II TNFRs), however, failed to become properly activated by soluble ligand trimers despite high affinity binding. The limited responsiveness of category II TNFRs to soluble TNFLs can be overcome by physical linkage of two or more soluble ligand trimers or, alternatively, by anchoring the soluble ligand molecules to the cell surface or extracellular matrix. This suggests that category II TNFRs have a limited ability to promote clustering of trimeric TNFL–TNFR complexes outside the context of cell–cell contacts. In this review, we will focus on three aspects on the relevance of receptor oligomerization for TNFR signaling: (i) the structural factors which promote clustering of free and liganded TNFRs, (ii) the signaling pathway specificity of the receptor oligomerization requirement, and (iii) the consequences for the design and development of TNFR agonists.

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“…For example, enhanced agonistic activity of anti-TRAILR2 antibodies have been reported for antibody variants with a heavy chain fused with a N- or C-terminal scFv anchoring domain [75,149]. Vice versa, N-terminal fusion of a TRAILR2-spcecific scFv domain to a MCSP- or FOLR1-specific IgG1 also resulted in increased anchoring-dependent agonism of the scFv-domain [150,151]. Noteworthy, in the case of the anti-MCSP anchored scFv:TRAILR2, there was further enhancement upon FcγR binding of the construct, suggesting that the agonistic potential of the TRAILR2-specific scFv domain was not fully unleashed.…”

Section: Next Generation Trail Death Receptor Agonists Based On Anmentioning

confidence: 99%

“…( A ) Structure of recently published bispecific anti-TRAILR1/2 antibody variants with anchoring-dependent agonism [75,150,151]. ( B ) Mode of action of an anti-TRAILR2 fusion protein with anchoring domain on the heavy chain.…”

Section: Figurementioning

confidence: 99%

Molecular Mode of Action of TRAIL Receptor Agonists—Common Principles and Their Translational Exploitation

Wajant

2019

Cancers

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its death receptors TRAILR1/death receptor 4 (DR4) and TRAILR2/DR5 trigger cell death in many cancer cells but rarely exert cytotoxic activity on non-transformed cells. Against this background, a variety of recombinant TRAIL variants and anti-TRAIL death receptor antibodies have been developed and tested in preclinical and clinical studies. Despite promising results from mice tumor models, TRAIL death receptor targeting has failed so far in clinical studies to show satisfying anti-tumor efficacy. These disappointing results can largely be explained by two issues: First, tumor cells can acquire TRAIL resistance by several mechanisms defining a need for combination therapies with appropriate sensitizing drugs. Second, there is now growing preclinical evidence that soluble TRAIL variants but also bivalent anti-TRAIL death receptor antibodies typically require oligomerization or plasma membrane anchoring to achieve maximum activity. This review discusses the need for oligomerization and plasma membrane attachment for the activity of TRAIL death receptor agonists in view of what is known about the molecular mechanisms of how TRAIL death receptors trigger intracellular cell death signaling. In particular, it will be highlighted which consequences this has for the development of next generation TRAIL death receptor agonists and their potential clinical application.

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A Single-Agent Dual-Specificity Targeting of FOLR1 and DR5 as an Effective Strategy for Ovarian Cancer

Cited by 29 publications

References 49 publications

Evaluation of FGFR1 as a diagnostic biomarker for ovarian cancer using TCGA and GEO datasets

Evaluation of FGFR1 as a diagnostic biomarker for ovarian cancer using TCGA and GEO datasets

Receptor Oligomerization and Its Relevance for Signaling by Receptors of the Tumor Necrosis Factor Receptor Superfamily

Molecular Mode of Action of TRAIL Receptor Agonists—Common Principles and Their Translational Exploitation

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