ID #425 A brain-penetrant PHGDH degrader induces metabolic and epigenetic dysregulation and drives tumor regression in diffuse midline glioma

Abstract

►Diffuse midline gliomas (DMGs) are uniformly lethal pediatric brain tumors that are driven by the H3K27M mutation. Since the brain is intrinsically deficient in amino acids, including serine, we investigated whether the H3K27M mutation rewires metabolism to facilitate tumor growth within this nutrient­restricted environment. Across murine and patient-derived DMG models, as well as patient tissue, we found that the H3K27M mutation upregulated the rate-limiting enzyme in serine synthesis, phosphoglycerate dehydrogenase (PHGDH). Both genetic ablation of PHGDH and treatment with a first-in-class molecular glue degrader (LXH-3-71) abolished serine synthesis from [U13C]-glucose in DMG cells. Loss of serine production, in turn, depleted nucleotides, sphingolipids, phospholipids, glutathione, and alpha-ketoglutarate. Mechanistically, the reduction in alpha-ketoglutarate, which is an obligate cofactor for histone demethylases, restored histone hypermethylation, thereby counteracting a key epigenetic consequence of the H3K27M mutation. In addition, the broader metabolic collapse led to oxidative stress and lipid peroxidation, resulting in ferroptotic cell death. Using in vivo stable-isotope tracing and spatial metabolomics, we confirmed that LXH-3-71 crossed the blood-brain barrier and abrogated serine synthesis in mice bearing intracranial DMG xenografts. Importantly, LXH-3-71 induced marked tumor regression and significantly prolonged survival in multiple intracranial DMG models in vivo. Finally, to develop a clinically translatable pharmacodynamic and response biomarker, we paired our therapy with non-invasive imaging. Deuterium metabolic imaging of glucose metabolism provided an early readout of response to LXH-3-71, preceding MRI-detectable changes and predicting survival benefit, in mice bearing intracranial DMG xenografts. Since deuterium metabolic imaging is clinically implementable and LXH-3-71 is brain penetrant, our therapy and imaging biomarker have the potential for clinical translation. Collectively, our studies mechanistically validate PHGDH as an H3K27M-induced metabolic vulnerability and present an integrated metabolic therapy and imaging strategy for DMGs.