SFEBES2026 Oral Communications Mechanisms and Management of Endocrine Disease (5 abstracts)
Sphingosine kinase 2 (SPHK2) inhibition as a therapeutic strategy for adrenocortical carcinoma (ACC)
Kanwal Asif 1 , Barbara Altieri 2 , James Pittaway 1 , Chris Smith 1 , Ruth Kwong 1 , Constanze Hantel 3 , Sandra Sigala 4 , Alfredo Berruti 4 , Silviu Sbiera 2 , Martin Fassnacht 2 , Leonardo Guasti 1 , Lou Metherell 1 & Rathi Prasad 1
1Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom; 2Division of Endocrinology and Diabetes, Dept. of Medicine, University Hospital, University of Würzburg, Würzburg, Germany; 3Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland; 4Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
Background: Sphingolipid metabolism plays a role in adrenal homeostasis, as evidenced by the association of sphingolipid enzyme deficiency with adrenal insufficiency. In contrast, high transcriptomic expression of several sphingolipid enzymes is associated with poor prognosis in adrenocortical carcinoma (ACC). This study is focused on SPHK2, high transcriptomic expression of which is associated with poor overall survival in ACC (analysis of the TCGA-ACC data).
Methods: Immunohistochemical staining of SPHK2 was undertaken in 125 ACC (where clinical data were available for correlation), 21 adrenocortical adenomas (ACA), and 5 normal adrenal tissues from University Hospital Würzburg. Lentiviral driven stable overexpression of SPHK2 was established in 3 ACC lines (H295R, TVBF-7, MUC-1) with cell proliferation, migration, response to mitotane treatment and selective SPHK2 inhibition assayed.
Results: SPHK2 expression was significantly higher in ACC compared to ACA but showed no correlation with established prognostic factors, clinical scores, or steroid production. Although there was a trend toward reduced overall survival with high SPHK2 expression, it did not reach statistical significance, and no impact was seen on progression or recurrence free survival. All three ACC cell lines (H295R, TVBF-7, MUC-1) express SPHK2. Overexpressing SPHK2 did not affect cell proliferation assayed at 72 hours in the 3 cell lines. SPHK2 overexpression did, however, promote cell migration in the H295R cell line. Opaganib (ABC294640), a selective SPHK2 inhibitor, reduced cell viability to a similar extent as mitotane in all three cell lines. Interestingly, SPHK2 overexpression in TVBF-7 cells induced mitotane resistance; this did not affect the susceptibility of the cells to SPHK2 inhibition.
Conclusion: SPHK2 inhibition, already in phase II clinical trials for other cancers, may present an alternative/adjunctive therapy in ACC. Further work is ongoing to identify the biological pathways disrupted by SPHK2 inhibition and determine how they differ from those targeted by mitotane.
Volume 117
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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