Glioblastoma (GBM) is the most common primary tumor of the CNS with limited treatment options and a poorclinical prognosis. Standard of care treatment, including surgical resection, radiation therapy and concurrenttemozolomide (TMZ) treatment followed by adjuvant TMZ, produces a median survival in newly diagnosed GBMof ~15 months. Tumor recurrence happens due to therapy resistant tumor cells; therefore, therapeutic strategiesthat improve tumor cell sensitivity to chemotherapy are needed to improve patient outcomes. TROY (TNFRSF19), a member of the TNF receptor superfamily, has recently been discovered to impact GBMprogression. Briefly, TROY expression increases with increasing glial tumor grade and inversely correlates withpatient survival. Increased expression of TROY stimulates GBM cell migration/invasion in vitro and in vivo andincreases resistance to TMZ or radiation in vitro, while knockdown of TROY expression inhibits cell invasion,increases sensitivity to TMZ, and prolongs survival in a murine patient-derived xenograft (PDX) model. Theseand additional studies indicate that TROY represents a potential novel therapeutic target for GBM. Propentofylline (PPF), a drug that has been studied in numerous clinical trials for several non-GBMindications, downregulates TROY, inhibits GBM invasion and increases sensitivity in vitro and in vivo to TMZand radiotherapy. PPF exhibits a well-characterized pharmacological profile, including good brain distributionand favorable safety metrics. Repurposing PPF could be faster to clinical trials, less risky and less costly thanthe traditional drug development pathway for new chemical entities. The primary goal of this proposal is to test the ability of PPF to sensitize GBM to TMZ. Secondary goalsinclude assessing: the necessity of TROY for PPF activity, the mechanisms of action for PPF-induced TROYdownregulation, and the impact of PPF treatment and TROY expression on tumor-promoting microglia. The following aims have been designed to answer these questions. Specific Aim 1: Test the ability of PPFto sensitize TMZ resistant GBM tumors to therapeutic treatment in intracranial PDX models and asyngeneic model. The ability of PPF to sensitize GBM cells to TMZ will be evaluated in five TMZ resistant PDXmouse models and one immunocompetent syngeneic model. IVIS-monitoring of tumor growth, duration ofsurvival as well as histopathological and molecular analysis of tumor and tumor microenvironment will beevaluated. Specific Aim 2: Characterize the cellular and molecular targets of PPF to predict clinicalresponsiveness. Live-cell automated imaging and molecular techniques will be used to help define the cellularand molecular targets of PPF. We will test the ability of PPF to sensitize a diverse panel of 20 human GBM PDXlines, representing varied molecular and prognostic subtypes, to TMZ treatment ex vivo and assess the effectsof PPF on microglia in vitro.
Public Health Relevance Statement: NARRATIVE
Glioblastoma (GBM) has poor clinical outcomes due to therapy-resistant tumor cells that lead to recurrence;
therefore, therapeutic strategies that enhance tumor cell chemosensitivity are essential for improved patient
outcomes. This proposal will evaluate if propentofylline, a clinically investigated, well-characterized repurposable
drug with good brain penetration and favorable safety metrics, increases sensitization of GBM tumor cells to
chemotherapy. This project could lead to a therapeutic strategy to extend survival times for GBM patients.
Project Terms: <3'5'-cyclic ester of AMP> | | | | | 