Abstract 1601: Potentiation of arsenic trioxide in glioblastoma
Authors: Shaffer Charles , Tang Nanyun , Hao Yue , Fink Karen , Snipes George , Mickey Bruce , Berens Michael 
Published: April 2023

Glioblastoma (GBM) is the most prevalent type of malignant tumor within the central nervous system. Possessing a five-year survival rate of 6.8%, new therapeutic options are a necessity in order to increase patient quality of life and survival outcomes. Arsenic trioxide (ATO) is an FDA approved drug for the treatment of relapsed or refractory acute promyelocytic leukemia. Clinical trials of ATO in combination with radiation and temozolomide show therapeutic effects in a modest subset of glioblastoma patients. ATO resistance in GBM cell lines is associated with MNK1-eIF4E upregulation. Additionally, diminished response to ATO is linked to resistance to oxidative stress via increased glutathione levels and NrF2 pathway expression. We sought to target each of these proposed mechanisms of resistance in order to develop a suite of compounds for use in combination therapies, with the goal of sensitizing GBM models to ATO. Six GBM PDX models were dosed with ATO at varying concentrations and monitored for the IC50 value of treatment. The cell lines exhibited a 20-fold difference in sensitivity, indicative of an underlying innate resistance to ATO. We performed drug dose response studies of patient-derived glioma cells treated with ATO in combination with the nutraceutical compounds Chrysin and Silibinin. Combination treatments using Chrysin and Silibinin showed potentiation of the cytotoxic effects of ATO. Confirmation of the mechanism for induced sensitivity to ATO will be explored by measuring shifts in glutathione content and susceptibility to oxidative stress in response to treatment using nutraceutical compounds. In addition, drug dosing with combination therapies utilizing the MAPK interacting serine/threonine kinase 1 (MNK1) inhibitors eFT-508 and EFT-206 also show synergistic effects in GBM cell lines. The eIF4E phosphorylation response to treatment of both ATO alone ATO MNK1i combination therapies will be monitored and analyzed for potential translational effects. Each of these compounds were selected based on safe use determined in clinical trials (MNK1 inhibitors) or over-the-counter availability (nutraceuticals). All four companion approaches show low pharmacological liabilities in crossing the blood brain barrier. Future studies involving these compounds will consist of testing these suggested combination therapies in vivo by observing their effectiveness in orthotopic, GBM tumor bearing mice. Identification and development of sensitization targets for ATO will allow for greater effectiveness of treatment and a greater potency of the drug in combating resistance which arises in response to treatment. Discovery of a predictive molecular signature of synergy from ATO and other targeted agents may pave the way for a successful clinical trial of these combinations in an identifiable subpopulation of GBM patients.

Citation Format: Charles Shaffer, Nanyun Tang, Yue Hao, Karen Fink, George Snipes, Bruce Mickey, Michael Berens. Potentiation of arsenic trioxide in 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 1601.