Abstract 6185: Debio 0123 is a selective WEE1 inhibitor that effectively penetrates the brain and demonstrates anti-tumor activity in preclinical models of glioblastoma

Abstract

Abstract Background: Glioblastoma (GBM) is one of the most aggressive and hard-to-treat cancers with a 5-year survival rate of 5.8%, in part due to the presence of the blood brain barrier (BBB) that prevents most therapeutics from reaching the tumors at efficacious concentrations. Debio 0123 is a WEE1 inhibitor that has previously shown significant preclinical efficacy in combination with DNA damaging agents or radiotherapy and is currently being investigated in phase 1 clinical studies either as a monotherapy or in combination with carboplatin. Herein we present data that demonstrates Debio 0123 effectively penetrates in to the brain and subsequently leads to anti-tumor activity in GBM models both in vitro and in vivo as a monotherapy or in combination with standard-of-care therapies (SOC). Methods: Radio- and chemo-sensitizing effects of Debio 0123 were evaluated in GBM cell lines in vitro using standard clonogenic assays or cytotoxicity assays. In vivo, distribution and bioanalysis studies were performed to determine the amount of Debio 0123 present in the different parts of the brain and intracranially implanted tumors. Efficacy of Debio 0123 as monotherapy or in combination with the SOC, temozolomide (TMZ), was further assessed in vivo in U87MG-luc intracranial or subcutaneous xenograft models. Results: In vitro, Debio 0123 in combination with radiation enhanced cell death in GBM cell lines and reduced TMZ IC50 in primary GBM cell lines. In vivo studies demonstrated substantial Debio 0123 brain penetration in mice, rats and monkeys, with mean brain-to-plasma concentration ratios of ~0.6 and 1.52 and 4, respectively. Furthermore, a mean tumor-to-plasma ratio of 0.62 was determined in orthotopically implanted brain tumors in mice. In efficacy studies, Debio 0123 administered at 30 or 60mg/kg every day for 28 days displayed significant anti-tumor activity in a GBM xenograft model U87-MG implanted in immunodeficient mice either subcutaneously, with up to 57.5% tumor growth inhibition, or orthotopically in the brain, with up to 73.7% tumor growth inhibition. Finally, efficacy of Debio 0123 in combination with TMZ was also assessed in intracranially transplanted U87-MG tumors. Here, TMZ was highly active, however, the combination of Debio 0123 and TMZ resulted in significantly enhanced anti-tumor activity leading to sustained complete regressions in 75% of animals for up to 100 days and was well tolerated throughout the 28-day treatment. Conclusion: These results demonstrate that following oral administration, Debio 0123 effectively crosses the BBB, has significant efficacy as a monotherapy and improves response to standard-of-care chemo or radiotherapy in preclinical models. Collectively, these data highlight Debio 0123 as a promising candidate for further clinical development in GBM patients that may provide improved response to SOC therapy. Citation Format: Luke Piggott, Noemie Luong, Frederic Massiere, Annett Kunze, Christophe Chardonnens, Anne Vaslin. Debio 0123 is a selective WEE1 inhibitor that effectively penetrates the brain and demonstrates anti-tumor activity in preclinical models of glioblastoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6185.