Abstract 4729: Incorporation of the antitumor compound 2OHOA and its metabolite into cell membranes

Abstract

Abstract The compound 2-hydroxyoleic (2OHOA) is a bioactive lipid molecule that has demonstrated an anti-tumor effect and high safety in cellular and animal models of glioblastoma multiform (GBM), considered the most aggressive and lethal of primary tumors of the central nervous system. Due to the poor prognosis of patients, with a median survival of 15 months, it is of great importance to develop new therapeutic strategies that improve the efficacy and safety of treatments to achieve complete remission of GBM. Granted orphan designation for the treatment of glioma in both the European Union and the United States, 2OHOA completed a phase I/IIA study on advanced solid tumors in adults (NCT01792310) showing pharmacological efficacy and safety. It is currently undergoing a phase IIB/III clinical trial on glioma patients (NCT04250922) in combination with the standard of care for glioma and a pediatric study on glioma and other solid tumors (NCT04299191).Here, we seek to define the mechanism of action of 2OHOA which is based on Membrane Lipid Therapy, an innovative approach that proposes the use of new molecules designed to modify the composition and lipid structure of the membrane and reverse a pathological lipid state. Therefore, we further investigated the effect of 2OHOA on membrane lipid composition when applied to human glioblastoma cell line by gas chromatography. In addition, we defined the 2OHOA’s effect on different components of the cell signaling pathway by Western Blot and PK in glioma patients.Our results demonstrated that 2OHOA is mostly incorporated in glioma cell membranes and poorly integrated in non-tumor cells, which would explain its specific effects and low side effects in GBM treatment. Moreover, we observed that after its incorporation, 2OHOA is metabolized to produce the compound C17:1n-9 by α-oxidation pathway, a key process for its anti-tumor effect in glioma cells. In addition, the C17:1n-9 metabolite impairs cell growth, reinforcing the 2OHOA activity. Finally, we examined this metabolite as a biomarker to predict and trace 2OHOA treatment, studying the pharmacokinetics of glioma patients treated with the drug in phase I/IIA and its accumulation in mice xenograft tumors. In conclusion, 2OHOA shows a different incorporation into cell membranes between tumor cells and non-tumor cells. Moreover, both 2OHOA and its metabolite C17:1n-9 have an antiproliferative effect and exhibit an appealing potential in the treatment of patients that develop GBM with unmet effective therapy. Citation Format: Roberto Beteta-Göbel, Raquel Rodríguez-Lorca, Paula Fernández-García, Pablo V. Escribá, Victoria Lladó. Incorporation of the antitumor compound 2OHOA and its metabolite into cell membranes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4729.