Targeting Radiation-Induced Glioma-Initiating Cells in Patient-Derived Glioblastoma

Background: Glioblastoma (GB) is a highly aggressive and treatment-resistant brain cancer with poor prognosis. Surgical resection followed by radiotherapy (RT) with the chemotherapeutic, temozolomide (TMZ), is the standard GB treatment; yet recurrence often occurs. GB is organized hierarchically with a small population of radiation-resistant glioma-initiating cells (GICs) that self-renew and drive tumor growth. Importantly, RT can induce a subset of cells from non-tumor-initiating into glioma-initiating cells (iGICs). Both GICs and iGICs contribute to tumor recurrence and therapy resistance. Thus, without effective elimination of non-tumorigenic GB and prevention or targeting of GICs, a cure is unlikely. The objective of this study is to identify small molecules that block RT-induced phenotypic conversion to occur. Method: We conducted a high-throughput screen of NCI Cancer Therapy Evaluation Program (CTEP) compounds with evidence for crossing the blood-brain-barrier. To identify stem-like or reprogramming of cells, we transduced GB cell lines representing each TCGA subtype to express a fluorescent reporter for proteasomal activity that distinguishes non-tumor-initiating cells from GICs. We tested CTEP agents at 10 different concentrations in combination with radiation. Results: Our results identified selumetinib as a candidate compound that effectively prevents radiation-induced phenotype conversion. Furthermore, in combination with radiation, selumetinib decreased stem cell maintenance in GICs with differential effects on viability in non-tumorigenic cells. Conclusion: Taken together, these findings suggest that repurposing FDA-approved compounds alongside current therapies may effectively target the cellular and molecular heterogeneity of GB. Furthermore, since these agents are already clinically approved, this approach can be rapidly implemented in the clinic.