TY - JOUR A1 - Eckhardt, Carolin A1 - Sbiera, Iuliu A1 - Krebs, Markus A1 - Sbiera, Silviu A1 - Spahn, Martin A1 - Kneitz, Burkhard A1 - Joniau, Steven A1 - Fassnacht, Martin A1 - Kübler, Hubert A1 - Weigand, Isabel A1 - Kroiss, Matthias T1 - High expression of Sterol-O-Acyl transferase 1 (SOAT1), an enzyme involved in cholesterol metabolism, is associated with earlier biochemical recurrence in high risk prostate cancer JF - Prostate Cancer and Prostatic Diseases N2 - Background Prostate cancer (PCa) is the most frequent cancer in men. The prognosis of PCa is heterogeneous with many clinically indolent tumors and rare highly aggressive cases. Reliable tissue markers of prognosis are lacking. Active cholesteryl ester synthesis has been associated with prostate cancer aggressiveness. Sterol-O-Acyl transferases (SOAT) 1 and 2 catalyze cholesterol esterification in humans. Objective To investigate the value of SOAT1 and SOAT2 tissue expression as prognostic markers in high risk PCa. Patients and Methods Formalin-fixed paraffin-embedded tissue samples from 305 high risk PCa cases treated with radical prostatectomy were analyzed for SOAT1 and SOAT2 protein expression by semi-quantitative immunohistochemistry. The Kaplan-Meier method and Cox proportional hazards modeling were used to compare outcome. Main Outcome Measure Biochemical recurrence (BCR) free survival. Results SOAT1 expression was high in 73 (25%) and low in 219 (75%; not evaluable: 13) tumors. SOAT2 was highly expressed in 40 (14%) and at low levels in 249 (86%) samples (not evaluable: 16). By Kaplan-Meier analysis, we found significantly shorter median BCR free survival of 93 months (95% confidence interval 23.6-123.1) in patients with high SOAT1 vs. 134 months (112.6-220.2, Log-rank p < 0.001) with low SOAT1. SOAT2 expression was not significantly associated with BCR. After adjustment for age, preoperative PSA, tumor stage, Gleason score, resection status, lymph node involvement and year of surgery, high SOAT1 but not SOAT2 expression was associated with shorter BCR free survival with a hazard ratio of 2.40 (95% CI 1.57-3.68, p < 0.001). Time to clinical recurrence and overall survival were not significantly associated with SOAT1 and SOAT2 expression CONCLUSIONS: SOAT1 expression is strongly associated with BCR free survival alone and after multivariable adjustment in high risk PCa. SOAT1 may serve as a histologic marker of prognosis and holds promise as a future treatment target. KW - prostate cancer KW - SOAT1 KW - cholesterol metabolism Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-271819 SN - 1476-5608 VL - 25 IS - 3 ER - TY - THES A1 - Eckhardt, Carolin T1 - Sterol O-Acyltransferasen als Zielmoleküle in der Tumortherapie sowie die klinische Relevanz ihrer Expression beim Prostatakarzinom T1 - Sterol-O-Acyl transferases as target molecules in tumor therapy and the clinical relevance of their expression in prostate cancer N2 - Sterol O-Acyltransferasen (SOATs) spielen eine zentrale Rolle im Cholesterinstoffwechsel von Zellen, indem sie die Veresterung von freiem Cholesterin und Speicherung in Lipid droplets katalysieren. In Tumorzellen findet häufig eine Aktivierung alternativer Pfade des Energiestoffwechsels, unter anderem des Lipidstoffwechsels statt. Präklinische und klinische Daten unterstützen den Mechanismus der SOAT-Inhibierung als Therapiekonzept für bestimmte Tumore. Eine genaue Kenntnis sowohl dieser Inhibitoren als auch der Expression des Zielmoleküls ist Voraussetzung für eine klinische Anwendung. Im ersten Teil dieser Arbeit wurde ein in-vitro SOAT-Aktivitätsassay etabliert und auf Grundlage dessen ein Vergleich der mittleren Hemmstärken ausgewählter SOAT-Inhibitoren gezogen. SOAT-transfizierte AD-293 Zellen sowie NCI-H295R Nebennieren-Zellen wurden mit dem fluoreszierenden 22-NBD-Cholesterin sowie den SOAT-Inhibitoren inkubiert und die Veresterung des Lipid-Analogons dann zunächst mikroskopisch und anschließend quantitativ mittels chromatographischer Auftrennung untersucht. Mitotane stellte sich mit einer IC50 von 1,3x10⁻⁶ M als schwächster SOAT-Inhibitor dar, gefolgt von Sandoz58-035 (IC50=1,4x10\(^{-8}\) M), ATR101 (IC50=3,1x10\(^{-9}\) M) und schließlich AZD3988 (IC50=8,8x10\(^{-10}\) M). Im zweiten Teil dieser Arbeit wurde die SOAT-Expression in Prostatektomiepräparaten von Hochrisiko Prostatakarzinom-Patienten mittels Immunhistochemie bestimmt. Eine starke SOAT1 Expression (SOAT H-Score 3) war sowohl in der univariaten als auch in der multivariaten Analyse hoch signifikant mit einem kürzeren biochemisch progressfreien Überleben der Patienten assoziiert unabhängig von etablierten Prognoseparametern [HR für den biochemischen Progress 2,33 (95%KI 1,48-3,68), p<0,001)]. Für SOAT2 war dies erwartungsgemäß nicht der Fall. SOAT1 scheint bei diesem bestimmten Kollektiv einen vielversprechenden Stellenwert als prognostischer Marker zu haben und könnte darüber hinaus zukünftig als Zielmolekül im Rahmen einer individualisierten Therapie des Prostatakarzinoms in Frage kommen. N2 - Sterol-O-Acyl transferases (SOATs) play a central role in cellular cholesterol metabolism by catalyzing the esterification of free cholesterol and storage in lipid droplets. In tumor cells, activation of alternative pathways of energy metabolism, including lipid metabolism, frequently occurs. Preclinical and clinical data support the mechanism of SOAT inhibition as a therapeutic concept for certain tumors. Accurate knowledge of both these inhibitors and the expression of the target molecule is a prerequisite for clinical application. In the first part of this work, an in vitro SOAT activity assay was established and a comparison of the mean inhibitory strengths of selected SOAT inhibitors was drawn based on this. SOAT-transfected AD-293 cells as well as NCI-H295R adrenal cells were incubated with the fluorescent 22-NBD cholesterol as well as the SOAT inhibitors, and the esterification of the lipid analogue was then examined first microscopically and then quantitatively by chromatographic separation. Mitotane turned out to be the weakest SOAT inhibitor with an IC50 of 1.3x10⁻⁶ M, followed by Sandoz58-035 (IC50=1.4x10\(^{-8}\) M), ATR101 (IC50=3.1x10\(^{-9}\) M) and finally AZD3988 (IC50=8.8x10\(^{-10}\) M). In the second part of this work, SOAT expression in prostatectomy specimens from high-risk prostate cancer patients was determined by immunohistochemistry. Strong SOAT1 expression (SOAT H-score 3) was highly significantly associated with shorter biochemical progression-free survival of patients independent of established prognostic parameters in both univariate and multivariate analysis [HR for biochemical progression 2.33 (95%CI 1.48-3.68), p<0.001)]. As expected, this was not the case for SOAT2. SOAT1 appears to have promising value as a prognostic marker in this particular collective and, moreover, could be considered as a future target in the context of individualized therapy of prostate cancer. KW - Sterol O-Acyltransferasen KW - SOAT KW - Hochrisiko Prostatakarzinom KW - SOAT Inhibitoren KW - Sterol-O-Acyl transferases KW - High risk prostate cancer KW - Cholesterol metabolism Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-243002 ER -