EXTH-34. ANTI-RETROVIRAL REPURPOSING FOR TREATMENT OF GLIOBLASTOMA

Abstract

Abstract Glioblastoma (GBM) is a WHO grade IV glioma whose heterogeneous nature and stem-like features contribute to resistance to conventional chemotherapeutics. Previously, antiretrovirals have been proposed as anti-neoplastic agents, but their clinical efficacy is limited. With the advent of modern anti-retroviral and combinatorial therapy, we sought to repurpose FDA-approved anti-retroviral drugs for glioblastoma. Here, we performed an unbiased screen of 16 antiretrovirals in 40 glioma cell lines using DEPMap for drug repositioning. We identified six potential antiretrovirals among several drug classes with significant anti-glioma activity: abacavir (ABC), lamivudine (LMV), raltegravir (RLT), darunavir (DAR), indinavir (IND), and etravirine (ETV). We validated the effects of six antiretrovirals on patient-derived GBM neurospheres (GBM28 and GBM43) and established glioma cell line (A172). The non-nucleoside reverse transcriptase inhibitor (ETV) had the lowest effective IC50 in chemoresistant PDX GBM neurospheres (15uM) and A172 cells (2.7uM). Synergy assessment of ETV with standard of care temozolomide (TMZ) demonstrated that these drugs work independently of one another (Bliss score of -0.39 and -0.83 in GBM 28 and GBM 43, respectively). In addition, we investigated ETV effect on stemness features and human endogenous retroviral elements. Western blot, immunofluorescence and qPCR showed a decrease in the stemness markers, OCT-4, and HERV-K env expression. Reverse transcriptase levels decreased significantly after sublethal ETV treatment (5uM) for 48 hours in the stem-like GBMNS but not in adherent A172 cells. Overall, several antiretroviral drugs could be repositioned for glioblastoma therapy. Given its ideal therapeutic index and ability to penetrate the blood-brain barrier, ETV may be a promising candidate for future clinical trials in neuro-oncology.