TMET-12. A pilot clinical trial to determine the safety and feasibility of dietary methionine restriction in five healthy adult volunteers (The METeor study)

Abstract Methionine is an essential amino acid supplied through the diet. While normal human cells can synthesize methionine from homocysteine, many malignancies, including glioblastoma, cannot do this. Thus, lowering blood methionine levels through dietary reduction could theoretically impair the growth of these tumors. Studies have shown that methionine depletion impairs the growth of glioblastoma cells in tissue cultures and in xenografts in mice. However, extending these findings to human glioma patients has been challenging due to the restrictive nature of a methionine-depleted diet and the unpleasant taste of necessary supplements. This pilot trial was designed to determine whether motivated individuals can comply with a 7-day period of dietary methionine restriction, and whether this duration of methionine restriction decreases serum levels of methionine. A registered dietician provided a structured meal plan for participants that limited dietary methionine intake to 2 mg/kg a day, while supplementing dietary protein using a methionine-depleted protein powder called Hominex-2. Plasma methionine and related metabolites were measured by liquid chromatography tandem mass spectrometry (LC-MS/MS) using a customized validated method. The coefficient of variation (CV) for all metabolites was <10%. It is anticipated that subjects on a methionine-restricted diet (MRD) will show a significant decrease in plasma methionine level, ranging from 40 – 60% of baseline values. Our goal is to use a methionine-depleted diet to improve outcomes for patients with recurrent glioblastoma. Lomustine, a standard therapy for recurrent GBM, is administered as a single oral dose every 6 weeks. Based on the half-life of the cytotoxic metabolites of lomustine, a 7-to-10-day period of methionine depletion should be sufficient to impair the metabolism of glioblastoma cells during their exposure to lomustine and might enhance its effectiveness. If successful, this pilot trial will lead to a phase 2 trial combining the diet with lomustine chemotherapy for recurrent glioblastoma patients.