RDNA-03. TARGETING THE EPIGENETIC REMODELING FACTOR FACT TO RADIOSENSITIZE GLIOBLASTOMA CANCER STEM CELLS

Abstract Radiotherapy remains standard of care for glioblastoma (GBM) but has limited efficacy due to the ability of cancer stem-like cells (CSCs) to drive tumor recurrence through their enhanced malignant properties (i.e., radioresistance, angiogenicity, and invasiveness). Our overall objective is to address an unmet clinical need by identifying strategies to overcome the inherent radioresistance of GBM CSCs and develop effective treatment modalities that will inclusively target this recurrence-driving subset of cells. We have previously shown that components of the cell cycle and DNA damage response (DDR) machinery are required for CSC malignancy. More recently, we reported that the facilitates chromatin transcription (FACT) complex, which serves to reorganize nucleosomes to facilitate RNA polymerase II (Pol II)-mediated transcription, is a key mediator of the CSC phenotype. FACT has also been reported to have a role in DNA replication and the DDR. We hence sought to evaluate the impact of FACT disruption using the small molecule inhibitor curaxin-137, with proven blood brain barrier penetration, on the ability of CSCs to tolerate irradiation induced DNA damage. We first combined curaxin-137 treatment with irradiation and followed the resolution of DNA damage by immunofluorescence for γH2A.X or 53BP1, markers of DNA damage. Results indicated that the combinatorial treatment induced a significantly greater amount of DNA damage that failed to be resolved in the CSCs. We next explored the impact of treatment on CSC viability. Results indicated that combination treatment with curaxin-137 did reduce clonogenic survival of CSCs. Ongoing studies aim at evaluating the in vivo efficacy of this treatment as a radiosentizing agent. The ability to identify paradigms that increase the radiosensitivity of CSCs will have immense therapeutic implications on reducing the propensity of CSCs to drive the malignant phenotype of GBM.