Structural Basis and Targeting of the Interaction between Fibroblast Growth Factor-inducible 14 and Tumor Necrosis Factor-like Weak Inducer of Apoptosis

Dhruv, Harshil D.; Loftus, Joseph C.; Narang, Pooja; Petit, Joachim; Fameree, Maureen; Burton, J. S.; Tchegho, Giresse; Chow, Donald; Yin, Holly; Al‐Abed, Yousef; Berens, Michael E.; Tran, Nhan L.; Meurice, Nathalie

doi:10.1074/jbc.m113.493536

Cited by 23 publications

(22 citation statements)

References 48 publications

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“…Given the recent efforts to develop TWEAK- or Fn14-targeted therapeutic agents for the treatment of cancer patients [2, 3, 5], including GBM patients [4, 41, 42, 49], our findings also suggest that the IDH1 mutation status might serve as an important eligibility criterion in GBM clinical trials involving Fn14-targeted agents. Furthermore, our results support a role for Fn14 in the more aggressive phenotype demonstrated by IDH1 WT tumors, consistent with our previous reports showing that Fn14 expression levels positively correlate with glioma grade and poor GBM patient survival [8].…”

Section: Discussionmentioning

confidence: 79%

Differential expression of the TWEAK receptor Fn14 in IDH1 wild-type and mutant gliomas

et al. 2018

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The TNF receptor superfamily member Fn14 is overexpressed by many solid tumor types, including glioblastoma (GBM), the most common and lethal form of adult brain cancer. GBM is notable for a highly infiltrative growth pattern and several groups have reported that high Fn14 expression levels can increase tumor cell invasiveness. We reported previously that the mesenchymal and proneural GBM transcriptomic subtypes expressed the highest and lowest levels of Fn14 mRNA, respectively. Given the recent histopathological re-classification of human gliomas by the World Health Organization based on isocitrate dehydrogenase 1 (IDH1) gene mutation status, we extended this work by comparing Fn14 gene expression in IDH1 wild-type (WT) and mutant (R132H) gliomas and in cell lines engineered to overexpress the IDH1 R132H enzyme. We found that both low-grade and high-grade (i.e., GBM) IDH1 R132H gliomas exhibit low Fn14 mRNA and protein levels compared to IDH1 WT gliomas. Forced overexpression of the IDH1 R132H protein in glioma cells reduced Fn14 expression, while treatment of IDH1 R132H-overexpressing cells with the IDH1 R132H inhibitor AGI-5198 or the DNA demethylating agent 5-aza-2′-deoxycytidine increased Fn14 expression. These results support a role for Fn14 in the more aggressive and invasive phenotype associated with IDH1 WT tumors and indicate that the low levels of Fn14 gene expression noted in IDH1 R132H mutant gliomas may be due to epigenetic regulation via changes in DNA methylation.

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Section: Discussionmentioning

confidence: 79%

Differential expression of the TWEAK receptor Fn14 in IDH1 wild-type and mutant gliomas

et al. 2018

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“…Fn14, the smallest member of the TNFR superfamily, is an emerging molecular target for GBM therapy [29, 42]. Fn14 is minimally expressed in normal human brain, but highly expressed in malignant gliomas with more aggressive and invasive characteristics [31].…”

Section: Discussionmentioning

confidence: 99%

Minimizing the non-specific binding of nanoparticles to the brain enables active targeting of Fn14-positive glioblastoma cells

et al. 2015

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A major limitation in the treatment of glioblastoma (GBM), the most common and deadly primary brain cancer, is delivery of therapeutics to invading tumor cells outside of the area that is safe for surgical removal. A promising way to target invading GBM cells is via drug-loaded nanoparticles that bind to fibroblast growth factor-inducible 14 (Fn14), thereby potentially improving efficacy and reducing toxicity. However, achieving broad particle distribution and nanoparticle targeting within the brain remains a significant challenge due to the adhesive extracellular matrix (ECM) and clearance mechanisms in the brain. In this work, we developed Fn14 monoclonal antibody-decorated nanoparticles that can efficiently penetrate brain tissue. We show these Fn14-targeted brain tissue penetrating nanoparticles are able to (i) selectively bind to recombinant Fn14 but not brain ECM proteins, (ii) associate with and be internalized by Fn14-positive GBM cells, and (iii) diffuse within brain tissue in a manner similar to non-targeted brain penetrating nanoparticles. In addition, when administered intracranially, Fn14-targeted nanoparticles showed improved tumor cell co-localization in mice bearing human GBM xenografts compared to non-targeted nanoparticles. Minimizing non-specific binding of targeted nanoparticles in the brain may greatly improve the access of particulate delivery systems to remote brain tumor cells and other brain targets.

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“…Several agents of this type have been described in the literature, including TWEAK-neutralizing mAbs, 24,118 Fn14-directed mAbs, 119,120 and the Fn14-binding small molecule L524-0366. 121 …”

Section: The Tweak-fn14 Axis and Glioblastomamentioning

confidence: 99%

The TWEAK receptor Fn14 is a potential cell surface portal for targeted delivery of glioblastoma therapeutics

et al. 2015

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Fibroblast growth factor-inducible 14 (Fn14; TNFRSF12A) is the cell surface receptor for the tumor necrosis factor (TNF) family member TNF-like weak inducer of apoptosis (TWEAK). The Fn14 gene is normally expressed at low levels in healthy tissues but expression is significantly increased after tissue injury and in many solid tumor types, including glioblastoma (GB; formerly referred to as ‘glioblastoma multiforme’ or GBM). GB is the most common and aggressive primary malignant brain tumor, and the current standard-of-care therapeutic regimen has a relatively small impact on patient survival, primarily because glioma cells have an inherent propensity to invade into normal brain parenchyma, which invariably leads to tumor recurrence and patient death. Despite major, concerted efforts to find new treatments, a new GB therapeutic that improves survival has not been introduced since 2005. In this review article, we summarize studies indicating that (i) Fn14 gene expression is low in normal brain tissue but up-regulated in advanced brain cancers and, in particular, in GB tumors exhibiting the mesenchymal molecular subtype, (ii) Fn14 expression can be detected in glioma cells residing in both the tumor core and invasive rim regions, with the maximal levels found in the invading glioma cells located within normal brain tissue, and (iii) TWEAK:Fn14 engagement as well as Fn14 overexpression can stimulate glioma cell migration, invasion, and resistance to chemotherapeutic agents in vitro. We also discuss two new therapeutic platforms that are currently in development that leverage Fn14 overexpression in GB tumors as a way to deliver cytotoxic agents to the glioma cells remaining after surgical resection while sparing normal healthy brain cells.

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Structural Basis and Targeting of the Interaction between Fibroblast Growth Factor-inducible 14 and Tumor Necrosis Factor-like Weak Inducer of Apoptosis

Cited by 23 publications

References 48 publications

Differential expression of the TWEAK receptor Fn14 in IDH1 wild-type and mutant gliomas

Differential expression of the TWEAK receptor Fn14 in IDH1 wild-type and mutant gliomas

Minimizing the non-specific binding of nanoparticles to the brain enables active targeting of Fn14-positive glioblastoma cells

The TWEAK receptor Fn14 is a potential cell surface portal for targeted delivery of glioblastoma therapeutics

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