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Glioblastoma (GBM) remains an incurable tumor with median overall survival of 15 months despite radiation and alkylating temozolomide (TMZ) chemotherapy. DNA damage response (DDR) pathways are among the most important key players of oncogenic mutations associated with resistance to both chemotherapy and radiation in GBM. The high frequency of alterations in DDR pathways in GBM suggests that its inhibition by DDR inhibitors may render GBM cells more susceptible to DNA damaging interventions. Here, we report the preclinical in vitro and in vivo activity of a novel, orally bioavailable Ataxia-telangiectasia mutated serine/threonine protein kinase and Rad3-related (ATR) inhibitor LR02 (Laevoroc Oncology) in a panel of 15 well-characterized glioma stem-like cells (GSCs). Effects on cell proliferation, survival and tumor formation were analyzed following treatment with LR02. Growth inhibition was time- and dose-dependent with a 3-day exposure resulting in a growth inhibitory IC50 (gIC50) in the low nM range in all the glioblastoma cell lines tested. LR02 inhibited growth of GSCs at IC50 values ranging from 500nmol/L to-~2umol/L. Additional studies showed that temozolomide sensitized GSC to LR02. Importantly, we demonstrate that MGMT promotor methylation status was associated with cellular response to LR02 treatment with preferential inhibition of cell growth in MGMT promotor methylated (MGMT deficient) cell lines. LR02 showed efficacy and survival benefit in a GSC262 (MGMT methylated) orthotopic model of GBM. Further administration of LR02 further enhanced the in vivo antitumor efficacy of temozolomide (TMZ) against GBM using the GSC262 model demonstrating that ATR inhibitor LR02 may enhance alkylating agent-mediated cytotoxicity and provide a novel treatment combination for GBM patients. Our present findings establish that the ATR inhibitor LR02 can specifically be used in tumors with MGMT deficiency when combined with alkylating chemotherapy. Further studies are ongoing to evaluate the potential of LR02 to overcome radiation and chemotherapy resistance in glioblastoma.

DDRE-33. PRECLINICAL THERAPEUTIC EFFICACY OF THE NOVEL BLOOD BRAIN BARRIER PENETRANT ATR INHIBITOR LR02 IN GLIOBLASTOMA