DRES-20. THE TNF RECEPTOR FAMILY MEMBER Fn14 IS HIGHLY EXPRESSED IN RECURRENT GLIOBLASTOMA (GBM) AND IN GBM PATIENT-DERIVED XENOGRAFTS WITH ACQUIRED TEMOZOLOMIDE RESISTANCE
Year: 2018
Type: article
Abstract: The current standard-of-care for patients with glioblastoma (GBM) consists of maximal safe surgical resection followed by high-dose radiation and concomitant oral chemotherapy using the DNA-alkylating agent temozolomide (TMZ). Despite this combination treatment, tumor recurrence is nearly universal. Recurrent GBM tumors tend to be more aggressive and treatment-resistant than their primary (i.e. newly diagnosed) counterparts. A better understanding of recurrent GBM biology would offer new opportunities for tailoring treatments following standard-of-care chemo-radiation therapy. Our prior work has demonstrated an important role for the TWEAK receptor Fn14 in GBM patho-biology. In the current study, we investigated Fn14 expression in recurrent GBM and in the setting of TMZ resistance. Fn14 mRNA expression levels in non-neoplastic brain, primary GBM, and recurrent GBM (post-chemotherapy and radiation) specimens were obtained from the TCGA data portal. Immunohistochemistry was performed using non-neoplastic brain as well as patient-matched primary and recurrent GBM specimens to examine Fn14 protein levels. Western blot analysis was used to compare Fn14 expression in parental TMZ-sensitive or matched TMZ-resistant patient-derived xenografts (PDXs) established from primary or recurrent tumor samples. The migratory capacity of control and Fn14-depleted TMZ-resistant GBM cells was assessed using the transwell migration assay. We found that Fn14 is more highly expressed in recurrent GBM tumors than their matched primary GBM counterparts. GBM PDX cells with acquired TMZ resistance have higher Fn14 levels and greater migration capacity than their corresponding parental TMZ-sensitive cells, and the migratory difference is due, at least in part, to Fn14 expression in the TMZ-resistant cells. CONCLUSIONS: This study demonstrates that the Fn14 gene is highly expressed in recurrent GBM and TMZ-resistant GBM PDX tumors. These findings suggest that Fn14 may be a valuable therapeutic target or drug delivery portal for treatment of recurrent GBM patients.
Source: Neuro-Oncology
Language: English
Subfield: Genetics (clinical)
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4237611766