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

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.

We conducted a high-throughput screen of NCI's Cancer Therapy Evaluation Program (CTEP) compounds with evidence for crossing the blood-brain-barrier. To identify "stemness" 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.

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.

Taken together, these findings suggest that repurposing FDA-approved compounds alongside current therapies may effectively target the cellular and molecular heterogeneity of GB-and because these agents are already clinically approved, this approach can be rapidly implemented in the clinic.