PhD Scientific Days 2021

Budapest, 7-8 July 2021

MO_II_L: Molecular Sciences II. Lectures

Identification of the mechanisms and predictive biomarkers in abiraterone resistance of prostate cancer

Anita Csizmarik1, Nikolett Nagy1, Dávid Keresztes1, Melinda Váradi1, Thilo Bracht2, Barbara Sitek2, Kathrine Witzke2, Martin Puhr3, Ilona Tornyi4, József Lázár5, László Takács4,5, Gero Kramer6, Sabina Sevcenco6, Agnieszka Maj-Hes6, Shahrokh F. Shariat6, Boris Hadaschik7, Péter Nyirády1, Tibor Szarvas1,7

1 Department of Urology, Semmelweis University, Budapest, Hungary
2 Medizinisches Proteom-Center, Ruhr University Bochum, Germany
3 Department of Urology, Medical University of Innsbruck, Austria
4 Department of Human Genetics, University of Debrecen, Hungary
5 Biosystems International Kft, Debrecen, Hungary
6 Department of Urology, Medical University of Vienna, Vienna, Austria
7 Department of Urology, University Hospital Essen, University of Duisburg-Essen, Germany

Text of the abstract

Introduction: Abiraterone (ABI) is an androgen biosynthesis inhibitor, which has been demonstrated to improve overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC). However, most mCRPC patients have baseline resistance or will develop acquired resistance to ABI. Currently, there are no validated biomarkers in a clinical practice to predict the outcome of ABI treatment. Therefore, serum biomarkers are urgently need to optimize therapy decisions.
Aims: We aimed to uncover the potential biomarkers of ABI resistance.
Methods: We used a comparative proteome analysis on three ABI-resistant (LNCaPabl-AR, DUCaP-AR, LAPC4-AR) and parental ABI sensitive (LNCaPabl, DUCaP, LAPC4) prostate cancer cell lines using liquid chromatography tandem mass spectrometry (LC-MS/MS) technique. We applied two bioinformatic filtering approaches in order to identify the most promising biomarker candidates. Four selected proteins (FSCN1, KLK2, AMARC, CTAG1A) were analysed in baseline serum samples of 100 ABI-treated patients by using the ELISA method. Serum concentrations were correlated with clinicopathological and survival data.
Results: Our proteome analysis identified an overall number of 68 at least 2-fold, significantly higher abundant proteins in ABI resistance cell lines. High FSCN1 and KLK2 serum levels were significantly associated with shorter overall survival. Multivariate analysis revealed high baseline PSA, KLK2 and FSCN1 levels as independent predictors of poor patients’ survival in ABI-treated CRPC patients (p=0.002, p=0.027 and p=0.004, respectively).
Conclusion:
Our results suggest that serum FSCN1 and KLK2 levels might be used as biomarkers for the identification of ABI resistant patients and may therefore help to optimize future clinical decision-making in mCRPC. Currently, functional cell culture experiments with siRNA mediated knockdown analysis are ongoing in order to assess the possible functional involvement of FSCN1 and KLK2 in ABI-resistance.
Funding:
This work was supported by NKFIH/PD 115616 and NVKP_16-1-2016-004. Supported by the ÚNKP-20-5-SE-1 and ÚNKP-20-3-II-SE-8 New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund. Tibor Szarvas was supported by János Bolyai Research Scholarship of the Hungarian Academy of Sciences.

University and Doctoral School

Semmelweis University, Károly Rácz Doctoral School of Clinical Medicine