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Abstract Heterozygous mutations in NADP‐dependent isocitrate dehydrogenases (IDH) define the large majority of diffuse gliomas and are associated with hypermethylation of DNA and chromatin. The metabolic dysregulations imposed by these mutations, whether dependent or not on the oncometabolite D‐2‐hydroxyglutarate (D2HG), are less well understood. Here, we applied mass spectrometry imaging on intracranial patient‐derived xenografts of IDH‐mutant versus IDH wild‐type glioma to profile the distribution of metabolites at high anatomical resolution in situ. This approach was complemented by in vivo tracing of labeled nutrients followed by liquid chromatography–mass spectrometry (LC‐MS) analysis. Selected metabolites were verified on clinical specimen. Our data identify remarkable differences in the phospholipid composition of gliomas harboring the IDH1 mutation. Moreover, we show that these tumors are characterized by reduced glucose turnover and a lower energy potential, correlating with their reduced aggressivity. Despite these differences, our data also show that D2HG overproduction does not result in a global aberration of the central carbon metabolism, indicating strong adaptive mechanisms at hand. Intriguingly, D2HG shows no quantitatively important glucose‐derived label in IDH‐mutant tumors, which suggests that the synthesis of this oncometabolite may rely on alternative carbon sources. Despite a reduction in NADPH, glutathione levels are maintained. We found that genes coding for key enzymes in de novo glutathione synthesis are highly expressed in IDH‐mutant gliomas and the expression of cystathionine‐β‐synthase (CBS) correlates with patient survival in the oligodendroglial subtype. This study provides a detailed and clinically relevant insight into the in vivo metabolism of IDH1‐mutant gliomas and points to novel metabolic vulnerabilities in these tumors.

Proper control of the phosphotyrosine content in signal transduction proteins is essential for normal cell behavior and is lost in many pathologies. Attempts to normalize aberrant tyrosine phosphorylation levels in disease states currently involve either the application of small compounds that inhibit tyrosine kinases (TKs) or the addition of growth factors or their mimetics to boost receptor-type TK activity. Therapies that target the TK enzymatic counterparts, the multi-enzyme family of protein tyrosine phosphatases (PTPs), are still lacking despite their undisputed involvement in human diseases. Efforts to pharmacologically modulate PTP activity have been frustrated by the conserved structure of the PTP catalytic core, providing a daunting problem with respect to target specificity. Over the years, however, many different protein interaction-based regulatory mechanisms that control PTP activity have been uncovered, providing alternative possibilities to control PTPs individually. Here, we review these regulatory principles, discuss existing biologics and proteinaceous compounds that affect PTP activity, and mention future opportunities to drug PTPs via these regulatory concepts.