The 1p/19q co-deletion induces targetable and imageable vulnerabilities in glucose metabolism in oligodendrogliomas

Background: The 1p/19q co-deletion is a hallmark of oligodendrogliomas. The goal of this study was to exploit the metabolic vulnerabilities induced by the 1p/19q co-deletion for the treatment and imaging of oligodendrogliomas. Methods: We used stable isotope tracing, mass spectrometry, and genetic and pharmacological approaches to interrogate [U-13C]-glucose metabolism in patient-derived oligodendroglioma models (SF10417, BT88, BT54, TS603, NCH612). We examined whether tracing [6,6'-2H]-glucose metabolism using deuterium metabolic imaging (DMI) provided an early readout of treatment response. Results: The glycolytic enzyme enolase 1 (ENO1; chromosome 1p36.23) was downregulated in patient-derived oligodendroglioma cells and patient tissue due to the 1p/19q co-deletion and histone hypermethylation. Conversely, inactivation of the CIC transcriptional repressor, driven by activated mitogen-activated protein kinase (MAPK) signaling, upregulated the ENO2 isoform specifically in oligodendrogliomas. Genetic ablation of ENO2 or pharmacological inhibition using POMHEX inhibited proliferation with nanomolar potency but was not cytotoxic to oligodendroglioma cells. Mechanistically, ENO2 loss abrogated [U-13C]-glucose metabolism to lactate but shunted glucose towards biosynthesis of serine and purine nucleotides, an effect that was driven by the rate-limiting enzyme for serine synthesis, phosphoglycerate dehydrogenase (PHGDH). Importantly, combining the PHGDH inhibitor D8 with POMHEX resulted in synthetic lethality in vitro and induced tumor regression in vivo. Furthermore, DMI of lactate production from [6,6'-2H]-glucose provided an early readout of response to combination therapy that preceded MRI-detectable alterations and reflected extended survival. Conclusions: We have identified ENO2 and PHGDH as metabolic vulnerabilities induced by the 1p/19q co-deletion in oligodendrogliomas and [6,6'-2H]-glucose as a non-invasive tracer of early response to therapy.