Abstract 5366: Propentofylline inhibits TROY/TNFRSF19 signaling to enhance therapeutic efficacy in invasive glioblastoma cells

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Glioblastoma (GBM) is the most common primary tumor of the CNS and carries a dismal prognosis. The aggressive invasion of GBM cells into the surrounding normal brain makes complete resection impossible, significantly increases resistance to the standard therapy regimen, and virtually assures tumor recurrence. Median survival for newly diagnosed GBM is 14.6 months and declines to 8 months for patients with recurrent GBM. New therapeutic strategies that target the molecular drivers of invasion are required for improved clinical outcome. We have demonstrated that TROY (TNFRSF19), a member of the TNFR super-family, plays an important role in GBM invasion and resistance. TROY expression increases with glial tumor grade and inversely correlates with patient survival. TROY stimulates GBM cell invasion and increases resistance to temozolomide (TMZ) and radiation treatment. Conversely, knockdown of TROY expression inhibits GBM cell invasion, increases sensitivity to temozolomide, and prolongs survival in an intracranial xenograft model. Propentofylline (PPF), an atypical synthetic methylxanthine compound, has been extensively studied in Phase II and Phase III clinical trials for Alzheimer's disease and vascular dementia where it has demonstrated blood-brain permeability and minimal adverse side effects. In this study, we demonstrated that PPF decreases TROY protein expression in glioma cells, and subsequently suppress activation downstream signaling effectors including AKT, NF-κB, and Rac1. PPF treatment of glioma cells also suppressed glioma cell migration and invasion, demonstrated by transwell migration assay and reduced membrane ruffling. Finally, PPF treatment increased vulnerability of glioma cells to Temozolomide (TMZ) and radiation. In summary, this study demonstrates that PPF provides a pharmacologic approach to target TROY to inhibit glioma cell invasion and reduce therapeutic resistance to TMZ and radiation. Citation Format: Harshil D. Dhruv, Serdar Tuncali, Alison Roos, Patrick Tomboc, Nathan Jameson, Ashley Chavez, Joseph Loftus, Michael E. Berens, Nhan L. Tran. Propentofylline inhibits TROY/TNFRSF19 signaling to enhance therapeutic efficacy in invasive glioblastoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5366. doi:10.1158/1538-7445.AM2015-5366