Endocrine Abstracts (2018) 59 OC1.5 | DOI: 10.1530/endoabs.59.OC1.5

In vivo and ex vivo metabolomics in succinate dehydrogenase deficient tumorigenesis

Ruth Casey1, Madhu Basetti2, Mary McLean2, Ben Challis3, Ferdia Gallagher2,3 & Eamonn Maher1

1Cambridge University, Cambridge, UK; 2Cancer Research UK Cambridge Institute, Cambridge, UK; 3Cambridge Univeristy NHS Foundation Trust, Cambridge, UK.

Mutations affecting the mitochondrial enzyme succinate dehydrogenase (SDH) are associated with a wide spectrum of tumours. SDH deficient tumours have a unique tumour metabolome due to the interruption of the citric acid cycle and accumulation of the ‘oncometabolite’ succinate, which drives tumourigenesis. Investigating the tumour metabolome of SDH deficient tumours has potential translational application. MRI spectroscopy (1H-MRS) was used for in vivo metabolomics analysis and a nuclear magnetic resonance spectroscopy technique; high resolution magic angle spinning, was employed for ex vivo analysis. Ex vivo analysis was performed on 40 tumours (8 gastrointestinal stromal tumours (GIST), 32 phaeochromocytoma/paraganglioma (PPGL)). Targeted metabolomics analysis of succinate, demonstrated that succinate was several folds higher in SDH deficient tumours compared to wild type (wt) tumours (P<0.001). Untargeted metabolomics analysis demonstrated that concentrations of lactate, glutamate, aspartate and branch chain amino acids, were significantly lowered in SDH mutated tumours compared to wt tumours. The detection of 2 hydroxyglutarate (2HG) accumulation in a single paraganglioma, heralded the subsequent discovery of a somatic IDH1 (R132C) mutation in that tumour. In vivo metabolomics analysis was performed on 12 patients (6 GIST, 5 PPGL, 1 non-functioning pituitary macroadenoma) A succinate peak was detected for 8/12 (66.7%) patients and succinate detection correlated with SDHB immunohistochemistry and or germline genetic status in 11/12 (92%) cases. 1H-MRS identified a succinate peak in two patients with metastatic GIST without a germline SDHx mutation but an identified somatic SDHC epimutation. Finally, we demonstrated that in vivo metabolomics has a role as a surrogate biomarker to validate therapeutic strategies in malignant SDH deficient disease as succinate accumulation was identified in a patient with a metastatic paraganglioma and a germline SDHB mutation before treatment with lutetium labelled peptide receptor radionuclide therapy, but no succinate was detectable in the same tumour deposit after four cycles of treatment.

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