TMET-08. Serine biosynthesis is a druggable metabolic vulnerability in diffuse midline gliomas

Abstract Diffuse midline gliomas (DMGs) are lethal pediatric brain tumors that are driven by a K27M mutation in histone H3 (H3K27M). We do not understand how the H3K27M mutation rewires DMG metabolism to facilitate growth within the metabolic constraints imposed by the brain. For instance, the brain is deficient in the amino acid serine, which is essential for the biosynthesis of molecules critical to proliferation (nucleotides, proteins, sphingolipids, phospholipids), redox balance (glutathione), and epigenetic reprogramming (S-adenosylmethionine). Here, we demonstrate the therapeutic potential of targeting serine biosynthesis in DMGs in vivo. Specifically, using murine and patient-derived cells and patient biopsies that differed only in H3K27M status, we demonstrated that H3K27M upregulated the expression of phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in serine synthesis from glucose. Next, we examined the therapeutic potential of targeting PHGDH in DMGs. Silencing PHGDH expression using ASOs or pharmacological degradation of PHGDH using a novel molecular glue (PHGDH-deg) abrogated serine synthesis from [U-13C]-glucose in patient-derived DMG cells. The resulting depletion of nucleotides, sphingolipids, phospholipids, glutathione, and S-adenosylmethionine inhibited proliferation and induced oxidative stress, leading to lipid peroxidation and cell death by ferroptosis. Notably, in vivo stable isotope tracing confirmed that PHGDH-deg penetrated the blood-brain barrier and inhibited [U-13C]-glucose metabolism to serine in mice bearing intracranial DMG xenografts. Importantly, PHGDH-deg induced tumor regression and significantly extended the survival of mice bearing intracranial DMG xenografts (BT245, 24-B7, 24-C2, QCTB-R059). Furthermore, deuterium metabolic imaging of glucose metabolism provided an early readout of response to PHGDH-deg that preceded MRI-detectable volumetric alterations and predicted extended survival in vivo. Since PHGDH-deg is brain penetrant and deuterium metabolic imaging is clinically applicable, our studies have the potential for clinical translation. In essence, we have mechanistically validated serine biosynthesis as a metabolic vulnerability and developed an integrated metabolic therapy and imaging strategy for DMGs.