Synthetic combination therapy for diffuse midline gliomas

PROJECT SUMMARY Diffuse midline gliomas (DMGs) are lethal brain tumors in children. Patient prognosis is very bleak with median overall survival of ~9 months. These tumors typically arise in delicate anatomical locations such as the brain stem that prohibit surgical resection. Radiation is the only standard of care and provides symptomatic relief.

However, disease control is transient, and children inevitably face tumor recurrence and premature death. There is a need for novel therapies for DMG patients, especially those that can be combined with radiation. Glutathione (GSH) is essential for scavenging reactive oxygen species generated by radiation. GSH is also

essential for the detoxification of methylglyoxal (MGO), a highly reactive metabolite that is spontaneously produced during glycolysis. MGO induces apoptosis by irreversibly damaging proteins and DNA, and cancer cells adapt to MGO production by upregulating expression of glyoxalase 1 (GLO1), which detoxifies MGO by

conjugation with GSH. Analysis of TCGA data as well as our preliminary studies with patient-derived DMG models indicate that GLO1 expression is upregulated in DMGs. Inhibiting GLO1 using the potent brain-penetrant GLO1 inhibitor S-p-bromobenzylglutathione cyclopentyl diester (BBG) abrogates MGO detoxification and inhibits

proliferation of patient-derived DMG cells. Importantly, while BBG alone arrests tumor growth in mice bearing orthotopic patient-derived DMGs, combined treatment with BBG and radiation induces tumor regression in vivo. Based on these results, in Aim 1, we will determine whether the combination of BBG and radiation is an

actionable therapeutic strategy in patient-derived DMG models. Successful translation of novel therapies is aided by the identification of imaging biomarkers that report on early response to therapy. Deuterium magnetic resonance spectroscopy is a novel, clinically translatable method of visualizing the metabolism of 2H-labeled substrates in vivo. Our preliminary studies indicate that BBG

downregulates lactate production from [6,6-2H]-glucose in DMGs. Therefore, in Aim 2, we will determine whether [6,6-2H]-glucose provides a readout of response to combined BBG and radiation, prior to MRI-detectable anatomical alterations, in mice bearing orthotopic DMGs in vivo. Our proposal is innovative because we will validate GLO1 as a druggable vulnerability in DMGs. This project

is significant because our studies will set the stage for translation of the combination of BBG and radiation to DMG patients. Concomitantly, [6,6-2H]-glucose will enable early assessment of efficacy in clinical trials and in patient management. In essence, by leveraging metabolism for therapy and for imaging treatment response, we

will deliver precision medicine that enhances outcomes and quality of life for DMG patients.