Chemosensitization of Glioblastoma by Propentofylline

总结

SUMMARY Glioblastoma (GBM) is the most common primary tumor of the CNS with limited treatment options and a poor clinical prognosis. Standard of care treatment, including surgical resection, radiation therapy and concurrent temozolomide (TMZ) treatment followed by adjuvant TMZ, produces a median survival in newly diagnosed GBM of ~15 months. Tumor recurrence happens due to therapy resistant tumor cells; therefore, therapeutic strategies that 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 GBM progression. Briefly, TROY expression increases with increasing glial tumor grade and inversely correlates with patient survival. Increased expression of TROY stimulates GBM cell migration/invasion in vitro and in vivo and increases 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. These and 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-GBM indications, downregulates TROY, inhibits GBM invasion and increases sensitivity in vitro and in vivo to TMZ and radiotherapy. PPF exhibits a well-characterized pharmacological profile, including good brain distribution and favorable safety metrics. Repurposing PPF could be faster to clinical trials, less risky and less costly than the 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 goals include assessing: the necessity of TROY for PPF activity, the mechanisms of action for PPF-induced TROY downregulation, 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 PPF to sensitize TMZ resistant GBM tumors to therapeutic treatment in intracranial PDX models and a syngeneic model. The ability of PPF to sensitize GBM cells to TMZ will be evaluated in five TMZ resistant PDX mouse models and one immunocompetent syngeneic model. IVIS-monitoring of tumor growth, duration of survival as well as histopathological and molecular analysis of tumor and tumor microenvironment will be evaluated. Specific Aim 2: Characterize the cellular and molecular targets of PPF to predict clinical responsiveness. Live-cell automated imaging and molecular techniques will be used to help define the cellular and molecular targets of PPF. We will test the ability of PPF to sensitize a diverse panel of 20 human GBM PDX lines, representing varied molecular and prognostic subtypes, to TMZ treatment ex vivo and assess the effects of PPF on microglia in vitro.