MDB-74. SERINE/GLYCINE METABOLISM REPRESENTS A NOVEL TARGETABLE THERAPEUTIC VULNERABILITY IN MYC-AMPLIFIED MEDULLOBLASTOMA

Abstract

Abstract BACKGROUND Medulloblastoma is the most frequent malignant brain tumour of childhood. Whilst advances in risk-stratification and upfront multimodal therapy have led to five-year survival rates around 70%, a subset of tumours remain refractory to current therapies. Group 3 medulloblastomas (MBGRP3) are enriched for amplification or overexpression of the proto-oncogene MYC which conveys a dismal prognosis (<10% survival), highlighting the urgent need for novel therapeutic strategies. Recent advances have revealed a role for metabolic reprogramming in MYC-amplified MBGRP3 tumorigenesis, providing novel opportunities for selective therapeutic targeting. METHODS & RESULTS To investigate MYC-dependent metabolic alterations in MBGRP3, we generated three independent isogenic MBGRP3 cell-based models with regulable MYC expression (iMBGRP3-MYC) using a doxycycline-inducible shRNA system. Using 1H high-resolution magic angle spectroscopy and stable isotope-resolved metabolomics, we identified upregulation of the de novo serine/glycine biosynthesis pathway (SGP), attributable to elevated expression of the rate-limiting enzyme PHGDH, as a novel therapeutic target. Genetic and pharmacological (NCT-503) inhibition of PHGDH induced greater cell death in MYC-expressing cells compared to MYC knockdown cells and increased survival across two independent MYC-amplified MBGRP3 mouse models. The decrease in tumour growth observed was moderate; we therefore hypothesised that a compensatory reliance on exogenous serine/glycine may play a role in sustaining tumour progression under therapy. To explore this, we investigated the impact of exogenous serine/glycine starvation on MBGRP3-MYC tumour development. Starvation resulted in a marked MYC-dependent reduction in cell viability in vitro across independent iMBGRP3-MYC models. Notably, dietary serine/glycine starvation was well-tolerated, delayed tumour progression, and increased survival (by 50%) in an MBGRP3-MYC mouse model (p=0.005), highlighting the metabolic plasticity of MYC-amplified tumours to utilise both de novo and exogenous serine/glycine sources to survive and proliferate. CONCLUSIONS These findings identify serine/glycine metabolism as a targetable therapeutic vulnerability within MYC-amplified MBGroup3 and a novel therapeutic strategy to treat this poor-prognosis disease group.