Glutamine antagonism as a new treatment approach in adrenocortical carcinoma

Vasileios Chortis; Conghui Yao; Claudio Ribeiro; Mesut Berber; Liam Kelley; Nagano Luis Fernando; Sathuwarman Raveenthiraraj; Pedro Vendramini; Carlone Diana L.; Haigis Marcia C.; Kleiton Silva-Borges; Breault David T.

doi:10.1530/endoabs.109.OC2.1

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Endocrine Abstracts (2025) 109 OC2.1 | DOI: 10.1530/endoabs.109.OC2.1

SFEBES2025 Oral Communications Endocrine Cancer and Late Effects (6 abstracts)

Glutamine antagonism as a new treatment approach in adrenocortical carcinoma

Vasileios Chortis ^1,2,3 , Conghui Yao ⁴ , Claudio Ribeiro ² , Mesut Berber ^2,3 , Liam Kelley ⁴ , Luis Fernando Nagano ⁵ , Sathuwarman Raveenthiraraj ^2,3 , Pedro Vendramini ^2,3 , Diana L. Carlone ^2,3 , Marcia C. Haigis ⁴ , Kleiton Silva-Borges ^2,3 & David T. Breault ^2,3,6

Author affiliations

¹Department of Metabolism and Systems Science, University of Birmingham, Birmingham, United Kingdom; ²Division of Endocrinology, Boston Children’s Hospital, Boston, USA; ³Department of Pediatrics, Harvard Medical School, Boston, USA; ⁴Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, USA; ⁵University of Sao Paulo, Sao Paulo, Brazil; ⁶Harvard Stem Cell Institute, Cambridge, USA

Deregulation of cell metabolism is a hallmark feature of cancer that remains underexplored in adrenocortical carcinoma (ACC), despite the urgent need for better medical treatment options. We employed a recently developed transgenic mouse model of ACC, driven by gain-of-function β-catenin and loss-of-function p53 mutations (BPCre), to characterize in vivo ACC metabolism and identify putative targetable vulnerabilities. We used a combination of targeted metabolomics by liquid chromatography-mass spectrometry and RNA-seq to compare tissue metabolism in BPCre ACC tumours to normal adrenals. We identified widespread metabolic dysregulation in ACC (64/176 polar metabolites significantly dysregulated, false discovery rate [FDR]<0.05); most prominent changes pertained to arginine, proline and glutamate metabolism, nucleotide and nucleotide sugar metabolism, and glutathione metabolism. Lipidomic analysis revealed extensive dysregulation of triglyceride metabolism. Orthogonal analysis by RNA-seq revealed congruent metabolic pathway alterations. Given the prominent dysregulation of several glutamine-dependent metabolic pathways in BPCre tumours, we hypothesized that glutamine catabolism may represent a targetable metabolic vulnerability in ACC. Pharmacological targeting of glutamine metabolism by the glutamine antagonist 6-Diazo-5-Oxo-L-Norleucine (DON) effected marked cytotoxicity against four mouse and human ACC cell lines (IC50 0.03-4.07 uM). The effect was rescued only by nucleoside substitution, suggesting that glutamine contribution to de novo nucleoside biosynthesis is the critical metabolic dependency in ACC. In vivo, treatment with the DON pro-drug JHU-083 achieved marked tumour growth inhibition (TGI) against subcutaneous mouse ACC implants in both immunocompetent (mean TGI 86%) and immunodeficient mice (mean TGI 67%), as well as against human NCI-H295R xenografts. Tumour immunophenotyping by flow cytometry revealed significantly increased infiltration with Natural Killer cells, likely potentiating the anti-tumour effect of JHU-083 in immunocompetent mice. Tissue metabolomics of JHU-083-treated implants revealed extensive depletion of purine metabolites. This works imparts new insights into ACC metabolism and provides pre-clinical evidence supporting glutamine antagonism as a new treatment approach in ACC.