Abstract 620: The response of human glioblastoma cells to the novel drug 1A-116 is dependent on the circadian clock

Abstract

Abstract Glioblastomas (GBM) account for almost half of the malignant central nervous system tumors and have the highest mortality rates with only about 5% of the adult patients surviving 5 years after diagnosis. Current therapy for GBM is generally very aggressive, combining chemotherapy, radiotherapy, and surgical removal and increased the life expectancy only from 11 to 14 months, but, almost no significant advances were made in the last decades. Taking this into account, more effective compounds and new strategies, such as chronotherapeutic ones, need to be developed. The novel drug 1A-116 specifically blocks the interaction of the Rho GTPase Rac1 with some of its activators (GEFs proteins, such as Tiam1) inhibiting cell motility and proliferation of GBM. To optimize the effectiveness of 1A-116 a chronotherapeutic approach was implemented in vitro by applying the drug at different circadian times to synchronized LN-229 human GBM cells. Cell cultures displayed a functional circadian clock measured by Bmal1-luc activity and BMAL1 protein expression. Expression of Tiam1 was also assessed, finding circadian expression rhythms. The effects of 1A-116 on either cell proliferation, motility and toxicity, were dependent on the circadian cellular clock. The preliminary in vivo studies consisted on treating nude mice with 1A or control at ZT3 or 12. We found that the median survival of the mice treated at ZT3 was 82 days and at ZT12 was 78 days. These results suggest that a chronopharmacological approach based on the drug 1A-116 is a feasible strategy to improve GBM treatment outcomes. Citation Format: Laura Lucia Trebucq, Goergina A. Cardama, Pablo Lorenzano Menna, Diego A. Golombek, Juan J. Chiesa, Luciano Marpegan. The response of human glioblastoma cells to the novel drug 1A-116 is dependent on the circadian clock [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 620.