Dávid Keresztes1, Thilo Bracht2, Barbara Sitek2, Martin Puhr3, Orsolya Módos1, Anita Csizmarik1, Nikolett Nagy1, Gero Kramer4, Shahrokh Shariat4, Péter Nyirády1, Tibor Szarvas1
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 Urology, Medical University of Vienna, Austria
Docetaxel (DOC) chemotherapy is a standard treatment for metastatic castration-resistant prostate cancer (CRPC). Rapidly expanding treatment options for CRPC provide reasonable alternatives for those who are resistant to DOC. Therefore, prediction of DOC-resistance has become of great clinical importance.
Our purpose is to identify protein biomarkers which may predict the efficiency of DOC-therapy.
First, a comparative proteome analysis on DOC-sensitive (parental, DU145) and resistant (DU145-DR) cell lines has been performed by using the liquid chromatography-mass spectrometry (LC-MS/MS) technique. Results were cross-referenced with published proteom data. NAMPT (nicotinamide phsophoribosyl transferase) was determined in pre-therapy serum samples of 99 DOC-treated CRPC patients by ELISA. In addition, in 25 patients serum samples before and during/at progression have been assessed. Serum NAMPT levels were correlated with clinical and survival data.
LC-MS/MS identified 157 significantly upregulated proteins in DOC-resistant DU145-DR cells. Cross-reference analysis with two published proteome data set identified four consequently upregulated proteins (NAMPT, FLNC, ANXA3, KCRB) in DOC-resistant DU145 cells. NAMPT protein level was 3.9-fold increased in DU145-DR compared to parental DU145 cells. Pre-treatment NAMPT serum levels were not associated with clinicopatological data. Cox-univariable and also multivariable analyses identified the presence of metastases, previous radical surgical treatment, high PSA and NAMPT levels as significant predictors of patients’ survival in CRPC (p=0.011, p=0.009, p=0.046 and p=0.022, respectively). NAMPT serum levels were elevated before and during/at disease progression.
Our results suggest that NAMPT might be involved in DOC resistance. Determination of serum NAMPT may contribute to the prediction of DOC-resistance and therefore may help to facilitate clinical decision-making regarding the type and timing of therapy for CRPC patients. DOC resistant patients might benefit from an early administration other systemic therapy modalities.
Doctoral school: Clinical Medicine (Beginning of the PhD studies: 09.2017)
Program: Urology (Uro-oncology)
Supervisor: Dr. Tibor Szarvas