ECE2018 Poster Presentations: Adrenal and Neuroendocrine Tumours Endocrine tumours and neoplasia (34 abstracts)
New cancer drug targets identified in adrenocortical carcinoma through gene expression profiling
Raimunde Liang 1 , Isabel Weigand 1 , Barbara Altieri 1, , Stefan Kircher 3 , Sonja Steinhauer 1 , Silviu Sbiera 1 , Matthias Kroiss 1, , Andreas Rosenwald 3 , Martin Fassnacht 1 & Cristina Ronchi 1,
1Division of Endocrinology, University Hospital of Wuerzburg, Wuerzburg, Germany; 2Division of Endocrinology, Catholic UNiersity of the Sacred Heart, Rome, Italy; 3Department of Pathology, University of Wuerzburg, Wuerzburg, Germany; 4Comprehensive Cancer Center Mainfranken, Wuerzburg, Germany; 5Insitute of Metabolism and System Research, University of Birmingham, Birmingham, UK.
Adrenocortical carcinomas (ACC) are associated with heterogeneous prognosis and limited treatment options for advanced stages. Until now no efficient targeted therapies have been identified. This study aims to identify possible new molecular drug targets for a future personalized therapeutic approach. We isolated good quality RNA from 40 formalin-fixed paraffin-embedded tumor samples (33 from primary surgery, 5 from local recurrences and 2 from distant metastasis) of ACC patients (26F&14M, median age 46 yrs). Gene expression of 84 known cancer drug targets was evaluated by RT2 Profiler PCR Array (Qiagen). Fold change (FC) was calculated with the 2^(-DDCT) formula using 5 housekeeper genes and 5 normal adrenal glands (NAG) as reference (overexpression by FC>2.0). The expression of selected candidates was validated at the protein level by immunohistochemistry in the same series. The 6 most frequently overexpressed genes were TOP2A (100% of cases, median FC=16.5), IGF2 (95%, FC=52.9), CDK1 (80%, FC=6.7), CDK4 (62%, FC=2.9), PLK4 (60%, FC=2.8) and PLK1 (52%, FC=2.3). Several members of AURK and HDAC gene families (e.g. the) were also overexpressed. mRNA expression of AURKA, CDC25A, CDK1, CDK2, HDCA2 and TOP2A positively correlated with ki67 proliferation index (all P<0.05). CDK1, CDK4, PLK1 and TOP2A were selected as candidates for validation by immunohistochemistry. Interestingly, nuclear staining of CDK1, CDK4 and PLK1 significantly correlated with mRNA expression (R=0.64, R=0.52 and R=0.55, respectively, all P<0.005). In conclusion, we identified by gene expression profiling interesting targetable genes that might serve as basis for personalized therapy in advanced ACC. The expression of these candidates might be investigated by immunohistochemistry in the clinical practice. For instance, CDK4 is overexpressed in several cancers and can be targeted by CDK/CDK6 inhibitors (e.g. palbociclib) that are currently tested in numerous clinical trials on solid tumors. Validation and functional studies on ACC cell lines are ongoing to confirm present results.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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