Targeting glioma stem cells with thyroid hormone suppression: Phase 1/2 trial of methimazole in patients with progressive grade 4 gliomas.

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2044 Background: Gaseous hydrogen sulfide (H2S), a by-product of cysteine metabolism, inhibits the growth of glioblastoma (GBM) cells and impairs GBM progression in mice. Likewise, H2S generation and sulfhydration are decreased in human GBM specimens as compared to non-tumor controls. Thus, boosting H2S production is a novel strategy for GBM treatment. Suppression of thyroid hormone (TH) signaling increases endogenous production of H2S. We hypothesize that methimazole-induced hypothyroidism will enhance the efficacy of chemotherapy in WHO grade 4 gliomas by boosting H2S production capacity (HPC) within the tumor. The goal of this trial is to provide proof of concept that suppression of TH signaling, via methimazole and subsequent augmentation of H2S synthesis and signaling, is feasible in patients with WHO grade 4 gliomas (G4G). Methods: This modified phase 1/2 study evaluates the safety and efficacy of methimazole + chemotherapy with pharmacodynamic correlates in patients with progressive G4G. The main objective is a 10% increase in HPC and a 1.5-fold increase in peripheral blood sulfhydration signaling (SS). Patients who are planned for a clinically-indicated resection receive pre-op (5-7 days) and post-op methimazole with the addition of investigator’s choice of chemotherapy 1 month after starting post op methimazole. Patients receive methimazole + chemotherapy until progression. Resected tumor will be assayed for HPC and for proteins relevant to H2S production. Peripheral blood lead-acetate assays for HPC and SS are obtained at baseline, pre-op, intra-op, post-op, before the addition of chemotherapy, and before each cycle of methimazole + chemo. Key eligibility criteria: progressive G4G for whom a clinically-indicated resection is planned, and normal thyroid function with no history of thyroid disease. Patients may have had unlimited prior regimens including bevacizumab. Results: To date six patients (4 male) ages 49-59 years have enrolled. At all time points tested post-methimazole treatment relative to baseline age/sex matched no-methimazole control patients, there were significant increases in plasma H2S production capacity (table). Conclusions: In this early cohort, it appears methimazole treatment in recurrent GBM patients enhances HPC on a systemic level. Next steps will be to measure sulfide signaling and sulfhydration alterations in patient tumor samples. The protocol is being modified to allow earlier addition (2 weeks) of post-op chemotherapy. Clinical trial information: NCT05607407 . [Table: see text]