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- adrenocortical carcinoma (20) (entfernen)
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- Medizinische Klinik und Poliklinik I (17)
- Graduate School of Life Sciences (3)
- Klinik und Poliklinik für Nuklearmedizin (3)
- Pathologisches Institut (3)
- Klinik und Poliklinik für Allgemein-, Viszeral-, Gefäß- und Kinderchirurgie (Chirurgische Klinik I) (2)
- Center for Computational and Theoretical Biology (1)
- Comprehensive Cancer Center Mainfranken (1)
- Institut für Funktionsmaterialien und Biofabrikation (1)
- Kinderklinik und Poliklinik (1)
- Medizinische Fakultät (1)
Purpose
Adrenal tumors represent a diagnostic and therapeutic challenge. Promising results have been obtained through targeting the cytochrome P450 enzymes CYP11B1 and CYP11B2 for molecular imaging, and [\(^{123/131}\)I]iodometomidate ([\(^{123/131}\)I]IMTO) has even been successfully introduced as a theranostic agent. As this radiopharmaceutical shows rapid metabolic inactivation, we aimed at developing new improved tracers.
Methods
Several IMTO derivatives were newly designed by replacing the unstable methyl ester by different carboxylic esters or amides. The inhibition of aldosterone and cortisol synthesis was tested in different adrenocortical cell lines. The corresponding radiolabeled compounds were assessed regarding their stability, in vitro cell uptake, in vivo biodistribution in mice, and their binding specificity to cryosections of human adrenocortical and non-adrenocortical tissue. Furthermore, a first investigation was performed in patients with known metastatic adrenal cancer using both [\(^{123}\)I]IMTO and the most promising compound (R)-1-[1-(4-[\(^{123/}\)I]iodophenyl)ethyl]-1H-imidazole-5-carboxylic acid azetidinylamide ([\(^{123}\)I]IMAZA) for scintigraphy. Subsequently, a first endoradiotherapy with [\(^{131}\)I]IMAZA in one of these patients was performed.
Results
We identified three analogues to IMTO with high-affinity binding to the target enzymes and comparable or higher metabolic stability and very high and specific accumulation in adrenocortical cells in vitro and in vivo. Labeled IMAZA exhibited superior pharmacokinetic and imaging properties compared to IMTO in mice and 3 patients, too. An endoradiotherapy with [\(^{131}\)I]IMAZA induced a 21-month progression-free interval in a patient with rapidly progressing ACC prior this therapy.
Conclusion
We developed the new radiopharmaceutical [\(^{123/131}\)I]IMAZA with superior properties compared to the reference compound IMTO and promising first experiences in humans.
Adjuvant platinum-based chemotherapy in radically resected adrenocortical carcinoma: a cohort study
(2021)
Background
After radical resection, patients with adrenocortical carcinoma (ACC) frequently experience recurrence and, therefore, effective adjuvant treatment is urgently needed. The aim of the study was to investigate the role of adjuvant platinum-based therapy.
Methods
In this retrospective multicentre cohort study, we identified patients treated with adjuvant platinum-based chemotherapy after radical resection and compared them with patients without adjuvant chemotherapy. Recurrence-free and overall survival (RFS/OS) were investigated in a matched group analysis and by applying a propensity score matching using the full control cohort (n = 268). For both approaches, we accounted for immortal time bias.
Results
Of the 31 patients in the platinum cohort (R0 n = 25, RX n = 4, R1 n = 2; ENSAT Stage II n = 11, III n = 16, IV n = 4, median Ki67 30%, mitotane n = 28), 14 experienced recurrence compared to 29 of 31 matched controls (median RFS after the landmark at 3 months 17.3 vs. 7.3 months; adjusted HR 0.19 (95% CI 0.09-0.42; P < 0.001). Using propensity score matching, the HR for RFS was 0.45 (0.29-0.89, P = 0.021) and for OS 0.25 (0.09-0.69; P = 0.007).
Conclusions
Our study provides the first evidence that adjuvant platinum-based chemotherapy may be associated with prolonged recurrence-free and overall survival in patients with ACC and a very high risk for recurrence.
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with an unfavorable prognosis. Despite the poor prognosis in the majority of patients, no improvements in treatment strategies have been achieved. Therefore, the discovery of new prognostic biomarkers is of enormous interest. Sterol-O-acyl transferase 1 (SOAT1) is involved in cholesterol esterification and lipid droplet formation. Recently, it was demonstrated that SOAT1 inhibition leads to impaired steroidogenesis and cell viability in ACC. To date, no studies have addressed the impact of SOAT1 expression on ACC prognosis and clinical outcomes. We evaluated SOAT1 expression by quantitative real-time polymerase chain reaction and immunohistochemistry in a tissue microarray of 112 ACCs (Weiss score ≥ 3) from adults treated in a single tertiary center in Brazil. Two independent pathologists evaluated the immunohistochemistry results through a semiquantitative approach (0–4). We aimed to evaluate the correlation between SOAT1 expression and clinical, biochemical and anatomopathological parameters, recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS). SOAT1 protein expression was heterogeneous in this cohort, 37.5% of the ACCs demonstrated a strong SOAT1 protein expression (score > 2), while 62.5% demonstrated a weak or absent protein expression (score ≤ 2). Strong SOAT1 protein expression correlated with features of high aggressiveness in ACC, such as excessive tumor cortisol secretion (p = 0.01), an advanced disease stage [European Network for the Study of Adrenal Tumors (ENSAT) staging system 3 and 4 (p = 0.011)] and a high Ki67 index (p = 0.002). In multivariate analysis, strong SOAT1 protein expression was an independent predictor of a reduced OS (hazard ratio (HR) 2.15, confidence interval (CI) 95% 1.26–3.66; p = 0.005) in all patients (n = 112), and a reduced RFS (HR 2.1, CI 95% 1.09–4.06; p = 0.027) in patients with localized disease at diagnosis (n = 83). Our findings demonstrated that SOAT1 protein expression has prognostic value in ACC and reinforced the importance of investigating SOAT1 as a possible therapeutic target for patients with ACC.
We have previously identified serum miR-483-5p as a preoperative diagnosis and prognosis biomarker for adrenocortical cancer (ACC). Here, we aimed to determine whether circulating miR-483-5p levels measured 3 months post-operatively distinguished patients with good prognosis (no recurrence for at least 3 years; NR3yrs) from patients with poor prognosis (recurrence or death within 3 years after surgery; R < 3yrs). We conducted a single-center retrospective analysis using sera from 48 patients with ACC that were initially non-metastatic and treated by surgery. Sera sampled within 3 months after surgery were available in 26 patients. MiR-483-5p absolute circulating levels were measured using quantitative PCR. Thirteen patients showed a recurrence before 3 years (=R < 3yrs). Thirteen patients showed no recurrence within 3 years, including 11 patients with a follow-up longer than 3 years (=NR3yrs). Serum miR-483-5p levels were higher in R < 3yrs than in NR3yrs: 1,541,990 ± 428,377 copies/mL vs. 388,457 ± 62,169 copies/mL (p = 0.002). Receiver operating characteristic analysis showed that a value of 752,898 copies/mL distinguished R < 3yrs from NR3yrs with 61.5% sensitivity (CI 31.6–86.1) and 100% specificity (CI 71.5–100) with an area under the curve of 0.853. Patients with a value below this threshold had a significantly longer recurrence-free and overall survival. In multivariate analysis, miR-483-5p provided the single best prognostic value for recurrence-free survival (RFS) (hazard ratio (HR) for recurrence 5.98, p < 0.011) but not for overall survival. Our study suggests that serum miR-483-5p is a potent early post-operative biomarker for ACC prognosis that might be a better predictor of RFS than currently used markers.
The SF-1 transcription factor target gene FATE1 encodes a cancer-testis antigen that has an important role in regulating apoptosis and response to chemotherapy in adrenocortical carcinoma (ACC) cells. Autoantibodies directed against FATE1 were previously detected in patients with hepatocellular carcinoma. In this study, we investigated the prevalence of circulating anti-FATE1 antibodies in pediatric and adult patients with adrenocortical tumors using three different methods (immunofluorescence, ELISA and Western blot). Our results show that a pervasive anti-FATE1 immune response is present in those patients. Furthermore, FATE1 expression is a robust prognostic indicator in adult patients with ACC and is associated with increased steroidogenic and decreased immune response gene expression. These data can open perspectives for novel strategies in ACC immunotherapy.
Impact of the Chemokine Receptors CXCR4 and CXCR7 on Clinical Outcome in Adrenocortical Carcinoma
(2020)
Chemokine receptors have a negative impact on tumor progression in several human cancers and have therefore been of interest for molecular imaging and targeted therapy. However, their clinical and prognostic significance in adrenocortical carcinoma (ACC) is unknown. The aim of this study was to evaluate the chemokine receptor profile in ACC and to analyse its association with clinicopathological characteristics and clinical outcome. A chemokine receptor profile was initially evaluated by quantitative PCR in 4 normal adrenals, 18 ACC samples and human ACC cell line NCI-H295. High expression of CXCR4 and CXCR7 in both healthy and malignant adrenal tissue and ACC cells was confirmed. In the next step, we analyzed the expression and cellular localization of CXCR4 and CXCR7 in ACC by immunohistochemistry in 187 and 84 samples, respectively. These results were correlated with clinicopathological parameters and survival outcome. We detected strong membrane expression of CXCR4 and CXCR7 in 50% of ACC samples. Strong cytoplasmic CXCR4 staining was more frequent among samples derived from metastases compared to primaries (p=0.01) and local recurrences (p=0.04). CXCR4 membrane staining positively correlated with proliferation index Ki67 (r=0.17, p=0.028). CXCR7 membrane staining negatively correlated with Ki67 (r=−0.254, p=0.03) but positively with tumor size (r=0.3, p=0.02). No differences in progression-free or overall survival were observed between patients with strong and weak staining intensities for CXCR4 or CXCR7. Taken together, high expression of CXCR4 and CXCR7 in both local tumors and metastases suggests that some ACC patients might benefit from CXCR4/CXCR7-targeted therapy.
Mitotane is the only approved drug for advanced adrenocortical carcinoma (ACC) and no biomarkers are available to predict attainment of therapeutic plasma concentrations and clinical response. Aim of the study was to evaluate the suitability of cytochrome P450(CYP)2W1 and CYP2B6 single nucleotide polymorphisms (SNPs) as biomarkers. A multicenter cohort study including 182 ACC patients (F/M = 121/61) treated with mitotane monotherapy after radical resection (group A, n = 103) or in not completely resectable, recurrent or advanced disease (group B, n = 79) was performed. CYP2W1*2, CYP2W1*6, CYP2B6*6 and CYP2B6 rs4803419 were genotyped in germline DNA. Mitotane blood levels were measured regularly. Response to therapy was evaluated as time to progression (TTP) and disease control rate (DCR). Among investigated SNPs, CYP2W1*6 and CYP2B6*6 correlated with mitotane treatment only in group B. Patients with CYP2W1*6 (n = 21) achieved less frequently therapeutic mitotane levels (>14 mg/L) than those with wild type (WT) allele (76.2% vs 51.7%, p = 0.051) and experienced shorter TTP (HR = 2.10, p = 0.019) and lower DCR (chi-square = 6.948, p = 0.008). By contrast, 55% of patients with CYP2B6*6 vs. 28.2% WT (p = 0.016) achieved therapeutic range. Combined, a higher rate of patients with CYP2W1*6WT+CYP2B6*6 (60.6%) achieved mitotane therapeutic range (p = 0.034). In not completely resectable, recurrent or advanced ACC, CYP2W1*6 SNP was associated with a reduced probability to reach mitotane therapeutic range and lower response rates, whereas CYP2B6*6 correlated with higher mitotane levels. The association of these SNPs may predict individual response to mitotane.
Platinbasierte Chemotherapie ist die effektivste Chemotherapie für das fortgeschrittene Nebennierenrindenkarzinom (ACC). Excision repair cross complementing group 1 (ERCC1) spielt eine entscheidende Rolle bei der Reparatur durch Platin entstandener DNA-Schäden. Zwei Studien die die Rolle von ERCC1 per Immunhistochemie als prädiktiver Marker für das Ansprechen auf platinbasierte Chemotherapie beim ACC untersuchten kamen zu sich widersprechenden Ergebnissen. Beide Studien nutzten den ERCC1-Antikörper Klon 8F1 der sich später als nicht spezifisch herausstellte. Das Ziel der Doktorarbeit war die Evaluation von ERCC1 mit einem neuen hoch spezifischen Antikörper in einer großen Kohorte von Patienten mit ACC.
Material und Methoden: 146 Patienten mit verfügbaren FFPE-Schnitten wurden eingeschlossen. Alle Patienten erhielten eine platinbasierte Chemotherapie im Median für 6 Zyklen, nämlich Cisplatin (n=131) oder Carboplatin (n=15), in den meisten Fällen in Kombination mit Etoposid (n=144 , Doxorubicin (n=131) und Mitotane (n=131). Die Immunhistochemische Färbung wurde mit dem neuen Antikörper Klon 4F9 durchgeführt. Der Zusammenhang zwischen ERCC1-Expression und klinischen Parametern, Therapieansprechen, progressionsfreiem Überleben und Gesamtüberleben wurde analysiert.
Ergebnisse: Eine hohe ERCC1-Expression wurde in 66% der Tumorproben beobachtet. Während der Chemotherapie zeigte sich bei 43 Pateinten ein Therapieansprechen (29,5%), bei 49 Patienten eine Stabilisierung der Erkrankung (33,6%), bei 8 Patienten ein gemischtes Ansprechen (5,5%) und bei 46 Pateinten ein Krankheitsprogress (31,5%), ohne Zusammenhang zur ERCC1-Expression. Auch zeigte sich kein signifikanter Zusammenhanf zwischen der ERCC1-Expression und dem progressionsfreien Überleben (Median 6.5 vs. 6 Monate, P=0.33, HR=1.23, 95%CI=0.82-2.0) oder dem Gesamtüberleben.
Zusammenfassung: Es besteht kein Zusammenhang zwischen der ERCC1-Expression und der Platinsensitivität beim Nebennierenrindenkarzinom. Somit werden andere Biomarker zur Therapieentscheidung benötigt.
Adrenocortical carcinoma (ACC) is a rare tumor and prognosis is overall poor but heterogeneous. Mitotane (MT) has been used for treatment of ACC for decades, either alone or in combination with cytotoxic chemotherapy. Even at doses up to 6 g per day, more than half of the patients do not achieve targeted plasma concentration (14–20 mg L\(^{-1}\)) even after many months of treatment due to low water solubility, bioavailability, and unfavorable pharmacokinetic profile. Here a novel MT nanoformulation with very high MT concentrations in physiological aqueous media is reported. The MT‐loaded nanoformulations are characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, and powder X‐ray diffraction which confirms the amorphous nature of the drug. The polymer itself does not show any cytotoxicity in adrenal and liver cell lines. By using the ACC model cell line NCI‐H295 both in monolayers and tumor cell spheroids, micellar MT is demonstrated to exhibit comparable efficacy to its ethanol solution. It is postulated that this formulation will be suitable for i.v. application and rapid attainment of therapeutic plasma concentrations. In conclusion, the micellar formulation is considered a promising tool to alleviate major drawbacks of current MT treatment while retaining bioactivity toward ACC in vitro.
Das Nebennierenrindenkarzinom ist ein seltener maligner, epithelialer Tumor mit einer jährlichen Inzidenz in Deutschland von 2 pro 1 Million Einwohnern. Es ist für etwa 0,2% aller Krebstodesfälle verantwortlich. Die Seltenheit der Erkrankung erschwert die Entwicklung wirksamer Therapieansätze erheblich. Erst in letzter Zeit gelang es, größere Patientenkohorten in kontrollierten Studien zu behandeln (Allolio et al. 2006) und größere Fallzahlen an Tumorgewebe wissenschaftlichen Untersuchungen zuzuführen. Erstmalig besteht damit auch die Möglichkeit, die Expression eventuell relevanter Proteine für moderne Therapiekonzepte auch an großen Fallzahlen zu untersuchen. Bislang liegen nur sehr lückenhafte diesbezügliche Studien vor. In der vorliegenden Arbeit wurde die Expression einiger möglicherweise therapeutisch relevanter Proteine mittels immunhistochemischer Analyse unter Zuhilfenahme der Tissue Microarray-(TMA)-Technik in einer großen Serie von 104 NNR-Ca untersucht und mit der von Nebennierenadenomen und normalem Nebennierengewebe verglichen. Insgesamt 9 verschiedene Proteine wurden immunhistochemisch dargestellt: Als wichtigster Befund wurde eine Überexpression der Alpha-methylacyl-CoA Racemase (AMACR) in 89% der untersuchten NNR-Ca festgestellt. Interessanterweise zeigte auch die Mehrzahl der untersuchten Nebennierenadenome (80%) zumindest eine schwache AMACR-Reaktivität, während die mituntersuchten normalen Nebennieren negativ blieben. Diese bislang nicht beschriebene Beobachtung gleicht den bekannten Befunden z.B. in der Prostata, in der sowohl die dort entstehenden Adenokarzinome, als auch deren Vorläuferläsionen (PIN) eine AMACR-Expression zeigen. EGFR, ein Tyrosinkinaserezeptor, auf den der bereits etablierte therapeutische Antikörper Cetuximab (Erbitux®) zielt, wurde in 49% der untersuchten NNR-Ca verstärkt exprimiert, so dass eine gegen den EGFR gerichtete Therapie in ausgewählten Fällen eine Behandlungsoption zu eröffnen scheint. Die Suche nach Mutationen in diesem potentiellen Zielprotein könnte weitere Ansatzpunkte für Wirkstoffe aufzeigen, Studien gibt es dazu bislang keine. Ähnliche Ergebnisse fanden sich in dieser Studie für VEGF, das von 19% der untersuchten NNR-Ca mäßig oder stark exprimiert wurde. Auch hier könnte eine entsprechende Therapie mit einem bereits kommerziell erhältlichen spezifischen Antikörper (Bevacizumab/Avastin®) in einem Teil der Fälle eine Behandlungsoption, ggf. auch als supportive Maßnahme, eröffnen. Angesichts der Expression von VEGF in nur rund einem Drittel der Fälle, wäre hier aber eine vorangehende Bestimmung des Expressionsstatus am Tumorgewebe unerläßlich. Weitere Untersuchungen sollten auch den VEGF-Rezeptor als möglichen Ansatzpunkt neuer Wirkstoffe, wie z.B. der Multi-Tyrosinkinase-Inhibitor Sunitinib [SU11248; SUTENTTM] (Le Tourneau et al., 2007), erforschen. Im Gegensatz dazu wurde eine wesentliche Expression weiterer untersuchter Proteine (CD117/C-kit, Her-2/neu, Östrogen- und Progesteronrezeptor) in NNR-Ca in dieser Studie nicht in einem Maße gefunden, welches in einer signifikanten Zahl von Fällen eine Therapieoption eröffnen würde. Eine immunhistochemisch bestimmbare Expression von p53, als Surrogatmarker für ein mutiertes p53-Gen wurde in 85% der untersuchten NNR-Ca nachgewiesen. Dies weist auf eine zentrale Bedeutung von p53-Mutationen in der Genese von NNR-Ca hin. (Reincke et al., 1994; Gicquel et al., 2001; Barzon et al.I, 2001; Soon et al., 2008) Auch die Proliferationsfraktion, bestimmt als Ki67-Index, war in den untersuchten Karzinomen gegenüber den Adenomen und den mitgeführten normalen Nebennieren deutlich erhöht, was das aggressive Wachstumspotential der Mehrzahl der NNR-Ca wiederspiegelt.