ECE2024 Poster Presentations Adrenal and Cardiovascular Endocrinology (95 abstracts)
Towards precision medicine in adrenocortical carcinoma; predicting response to mitotane using proteomics
Charlotte Vietor 1,2 , Anand Iyer 1 , Peter van Koetsveld 1 , Fadime Dogan-Oruc 1 , Lona Moradi-Zeyenedpour 3 , Gaston Franssen 2 , Cornelis Verhoef 2 , Tessa van Ginhoven 2 , Theo Luider 3 , Richard Feelders 1 & Leo Hofland 1
1Erasmus Medical Center and Erasmus MC Cancer Institute, Department of Internal Medicine, section Endocrinology, Rotterdam, Netherlands; 2Erasmus Medical Center and Erasmus MC Cancer Institute, Department of Surgery, Rotterdam, Netherlands; 3Erasmus Medical Center and Erasmus MC Cancer Institute, Laboratory of Neuro-Oncology/Clinical & Cancer Proteomics, Rotterdam, Netherlands
Background: Adrenocortical carcinoma (ACC) is a rare but devastating malignancy (5-year survival 18–57%), with limited treatment options. Currently, mitotane is the first-line medical treatment for metastatic ACC and is used in the adjuvant setting after surgery to prevent recurrence. Mitotane is an adrenolytic drug that is thought to act by disruption of mitochondria with subsequent activation of apoptosis. However, mitotane treatment comes with many drawbacks, such as severe side-effects and contralateral adrenal gland destruction, whilst both clinical and in vitrostudies have shown that it is only effective in 25–30% of ACC tumors. We performed a proteomics-based analysis of ACC tissues previously characterized in vitroas responders, partial responders and non-responders to mitotane, with the aim of identifying tissue biomarkers to improve future patient selection for mitotane therapy.
Methods: Protein lysates were obtained from fresh-frozen ACC samples (n=13 responders, n=10 partial responders, n=7 non-responders). Label-free liquid chromatography–mass spectrometry shotgun proteomics was performed on these samples. Differential protein abundance was assessed using two statistical methods (DESeq2 and spectral index), followed by pathway analysis using STRING.
Results: On average, 2628 proteins were identified per tumor sample. We found 25 proteins (84% being mitochondrial(-related)) with lower expression in responders compared to non-responders with both statistical methods. Pathway analysis revealed involvement of these proteins in mitochondrial fusion, mitochondrial membrane organization and mitochondrial fatty-acid beta-oxidation. In contrast, only four proteins were higher expressed in responders compared to non-responders.
Conclusion: Mitochondria-associated proteins are differentially expressed in ACC of patients who respond well to mitotane therapy compared to non-responders, fitting well with mitochondria being the presumed target of mitotane. Immunohistochemical validation is necessary to further explore the potential of specific proteins to serve as a biomarker for mitotane treatment response. Furthermore, the mechanism behind the relative upregulation of mitochondrial proteins in non-responders and whether there is a causal relationship with mitotane sensitivity remains to be elucidated.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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