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

Abstract

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.

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

“…We recently reported that the highest level of Fn14 mRNA expression occurred in mesenchymal subtype tumors [4]. However, this prior analysis utilized a relatively small GBM subtype sample size and did not distinguish between IDH1 WT and R132H mutant tumors.…”

“…In the setting of glioblastoma (GBM), the most prevalent and lethal form of adult brain cancer [6, 7], elevated Fn14 expression is associated with poor patient survival [8]. Four major transcriptional subtypes of GBM— classical, mesenchymal, neural and proneural—have been identified [9–11] and we reported previously that Fn14 mRNA was expressed at the highest levels in the more invasive and aggressive mesenchymal subtype tumors [4]. Glioma cell invasion into normal brain parenchyma is a hallmark of GBM pathophysiology and generally leads to tumor recurrence [6, 7].…”

“…Glioma cell invasion into normal brain parenchyma is a hallmark of GBM pathophysiology and generally leads to tumor recurrence [6, 7]. Interestingly, glioma cells located in the invasive rim express Fn14 at higher levels than those cells residing in the tumor core [8, 12], and TWEAK:Fn14 engagement as well as Fn14 overexpression can trigger glioma cell invasion in vitro and in vivo [4, 8, 12, 13]. …”

“…Recent work has shown that forced overexpression of the IDH1 R132H protein in glioma cells reduces migration [28] and invasion [28, 29] in vitro. Given the role that Fn14 may play in promoting glioma cell invasion [4, 8, 12, 13], we investigated Fn14 gene expression levels in IDH1 WT and R132H mutant low-grade gliomas (LGGs) and GBM tumors as well as IDH1 R132H-overexpressing glioma cell lines. We report that resected gliomas and glioma cell lines carrying an IDH1 R132H mutation express Fn14 at relatively low levels compared to their IDH1 WT counterparts, supporting a possible link between low Fn14 levels, reduced cell invasion, and improved patient prognosis associated with the IDH1 mutation.…”

Repurposing platinum-based chemotherapies for multi-modal treatment of glioblastoma

“…NPs targeted to Fn14-positive GBM cells using a monoclonal antibody improved NP tumor localization and internalization. 48,68 Thus, a similar targeting strategy may enhance the delivery of platinum compounds specifically to GBM cells, improving efficacy and minimizing toxicity.…”