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Pancreatic Neoplasms: HELP
Articles by Alexander O. König
Based on 6 articles published since 2010
(Why 6 articles?)
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Between 2010 and 2020, Alexander König wrote the following 6 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Current Standard and Future Perspectives in First- and Second-Line Treatment of Metastatic Pancreatic Adenocarcinoma. 2016

Ellenrieder, Volker / König, Alexander / Seufferlein, Thomas. ·Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen, Germany. ·Digestion · Pubmed #27438590.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a median 5-year survival of <8%. At the time of diagnosis, a vast majority of pancreatic cancer patients were found to be with either metastatic spread of the disease or locally advanced tumors. Despite relatively low efficacy, gemcitabine administration was the first choice chemotherapeutic strategy in advanced PDAC for many years. In the last 5 years, however, our understanding of pancreatic carcinogenesis has improved dramatically and with this our therapeutic options have expanded significantly. SUMMARY: With the FOLFIRINOX protocol or the combination of gemcitabine and nab-paclitaxel, 2 novel and more effective chemotherapeutic regimens have been introduced in clinical routine, which increased the overall survival by 4-5 months in the palliative situation. Most recently, we learned that both regimens can be modified and dosages can be adapted in older patients without significant loss of efficacy. Additionally, novel application strategies such as nanoparticle fused liposomal irinotecan along with 5-FU/LV provided convincing results in patients previously treated with gemcitabine. Current preclinical and clinical trials investigate efficacy and tolerability of novel drugs aiming at the inhibition of key inflammatory pathways, for example, JAK-STAT signaling, or the tumor surrounding desmoplasia. Prospectively, immunovaccination approaches or immune checkpoint inhibition appears as promising strategies in the near future, particularly when combined with epigenetic drugs in advanced PDAC patients. In this 'to-the-point' article, we review the current standard and summarize the most recent and encouraging advances in cytostatic PDAC treatment. KEY POINTS: (1) FOLFIRINOX and nab-paclitaxel/gemcitabine as first-line treatment regime significantly increase survival in patients with advanced PDAC; (2) Selection of appropriate treatment regime depends on patient performance, comorbidity, and toxicity; (3) PDAC patients will benefit from second-line chemotherapy and selection of appropriate regimes depends on first line therapy and patient criteria; (4) Future therapeutic strategies in advanced PDAC will respect molecular tumor profiling and other biomarkers.

2 Review Primers on molecular pathways--the NFAT transcription pathway in pancreatic cancer. 2010

König, Alexander / Fernandez-Zapico, Martin E / Ellenrieder, Volker. ·Signal Transduction and Transcription Laboratory, Department of Gastroenterology and Endocrinology, Philipps-University of Marburg, Marburg, Germany. ·Pancreatology · Pubmed #20720442.

ABSTRACT: The calcineurin-responsive nuclear factor of activated T cells (NFAT) family of transcription factors was originally identified as a group of inducible nuclear proteins, which regulate transcription during T lymphocyte activation. However, following their initial discovery, a multitude of studies quickly established that NFAT proteins are also expressed in cells outside the immune system, where they participate in the regulation of the expression of genes influencing cell growth and differentiation. Ectopic activation of individual NFAT members is now recognized as an important aspect for oncogenic transformation in several human malignancies, most notably in pancreatic cancer. Sustained activation of the Ca(2+)/calcineurin/NFAT signaling pathway has emerged as a powerful regulatory principle governing pancreatic cancer cell growth. Activated NFAT proteins form complexes with key oncogenic proteins to regulate the transcription of master cell cycle regulators and proteins with functions in cell survival, migration and angiogenesis. This review pays particular attention to recent advances in our understanding of how the NFAT transcription pathway controls gene expression during development and progression of pancreatic cancer. and IAP.

3 Article A Blood-Based Multi Marker Assay Supports the Differential Diagnosis of Early-Stage Pancreatic Cancer. 2019

Berger, Andreas W / Schwerdel, Daniel / Reinacher-Schick, Anke / Uhl, Waldemar / Algül, Hana / Friess, Helmut / Janssen, Klaus-Peter / König, Alexander / Ghadimi, Michael / Gallmeier, Eike / Bartsch, Detlef K / Geissler, Michael / Staib, Ludger / Tannapfel, Andrea / Kleger, Alexander / Beutel, Alica / Schulte, Lucas-Alexander / Kornmann, Marko / Ettrich, Thomas J / Seufferlein, Thomas. ·Ulm University, Department of Internal Medicine I, Albert-Einstein-Allee 23, 89081 Ulm, Germany. · Ruhr-University Bochum, Division of Hematology, Oncology and Palliative Care, Gudrunstr. 56, 44791 Bochum, Germany. · Ruhr-University Bochum, Department of Surgery, Gudrunstr. 56, 44791 Bochum, Germany. · Technical University Munich, Department of Internal Medicine I, Ismaninger Str. 22, 81675 Munich, Germany. · Technical University Munich, Department of Surgery, Ismaninger Str. 22, 81675 Munich, Germany. · University Medical Center Goettingen, Department of Gastroenterology and Gastrointestinal Oncology, Robert-Koch-Str. 40, 37075 Goettingen, Germany. · University Medical Centre Goettingen, Department of General, Visceral and Paediatric Surgery, Robert-Koch-Str. 40, 37075 Goettingen, Germany. · Philipps University Marburg, Department of Gastroenterology and Endocrinology, Baldingerstraße, 35043 Marburg, Germany. · Philipps University Marburg, Department of Visceral, Thoracic and Vascular Surgery, Baldingerstrasse, 35041, Marburg, Germany. · Esslingen Hospital, Department of Internal Medicine, Oncology/Hematology, Gastroenterology, Hirschlandstr. 97, 73730 Esslingen, Germany. · Esslingen Hospital, Department of General and Visceral Surgery, Hirschlandstr. 97, 73730 Esslingen, Germany. · Ruhr-University Bochum, Department of Pathology, Buerkle-de-la-Camp-Platz 1, 44789 Bochum, Germany. · Ulm University, Department of General and Visceral Surgery, Albert-Einstein-Allee 23, 89081 Ulm, Germany. ·Theranostics · Pubmed #30867830.

ABSTRACT: The most frequent malignancy of the pancreas is the pancreatic ductal adenocarcinoma (PDAC). Despite many efforts PDAC has still a dismal prognosis. Biomarkers for early disease stage diagnosis as a prerequisite for a potentially curative treatment are still missing. Novel blood-based markers may help to overcome this limitation. Methods: Prior to surgery plasma levels of thrombospondin-2 (THBS2), which was recently published as a novel biomarker, and CA19-9 from 52 patients with histologically proven PDAC were determined, circulating cell-free (cfDNA) was quantified. 15 patients with side-branch IPMNs without worrisome features and 32 patients with chronic pancreatitis served for comparison. Logit (logistic regression) models were used to test the performance of single biomarkers and biomarker combinations. Results: CA19-9 and THBS2 alone showed comparable c-statistics of 0.80 and 0.73, respectively, improving to 0.87 when combining these two markers. The c-statistic was further increased to 0.94 when combining CA19-9 and THBS2 with cfDNA quantification. This marker combination performed best for all PDAC stages but also for PDACs grouped by stage. The greatest improvement over CA19-9 was seen in the group of stage I PDAC, from 0.69 to 0.90 for the three marker combination.

4 Article Neoadjuvant plus adjuvant or only adjuvant nab-paclitaxel plus gemcitabine for resectable pancreatic cancer - the NEONAX trial (AIO-PAK-0313), a prospective, randomized, controlled, phase II study of the AIO pancreatic cancer group. 2018

Ettrich, Thomas J / Berger, Andreas W / Perkhofer, Lukas / Daum, Severin / König, Alexander / Dickhut, Andreas / Wittel, Uwe / Wille, Kai / Geissler, Michael / Algül, Hana / Gallmeier, Eike / Atzpodien, Jens / Kornmann, Marko / Muche, Rainer / Prasnikar, Nicole / Tannapfel, Andrea / Reinacher-Schick, Anke / Uhl, Waldemar / Seufferlein, Thomas. ·Department of Internal Medicine I, University of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany. · Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité University Medicine Berlin, Hindenburgdamm 30, 12200, Berlin, Germany. · Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Goettingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany. · Department of Oncology/Hematology, Fulda Hospital, Pacelliallee 4, 36043, Fulda, Germany. · Department of General and Visceral Surgery, University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany. · Department of Hematology and medical oncology, Johannes-Wesling-Klinikum Minden, Hans-Nolte-Straße 1, 32429, Minden, Germany. · Department of Internal Medicine, Oncology/Hematology, Gastroenterology, Esslingen Hospital, Hirschlandstr. 97, 73730 Esslingen, Esslingen, Germany. · Department of Internal Medicine II, Technical University Munich, Ismaninger Str. 22, 81675, Munich, Germany. · Department of Gastroenterology and Endocrinology, University of Marburg, Baldingerstraße, 35043, Marburg, Germany. · Department of Medical Oncology and Hematology, Niels-Stensen-Kliniken, Alte Rothenfelder Str. 23, 49124, Georgsmarienhütte, Germany. · Department of General and Visceral Surgery, University of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany. · Institute of Epidemiology and Medical Biometry, University of Ulm, Schwabstrasse 13, 89081, Ulm, Germany. · Department of Oncologie, Asklepios Klinik Barmbek, Rübenkamp 220, 22291, Hamburg, Germany. · Department of Pathology, Ruhr-University Bochum, Bürkle-de-la-Camp-Platz 1, 44789, Bochum, Germany. · Department of Internal Medicine, Ruhr-University Bochum, Gudrunstr. 56, 44791, Bochum, Germany. · Department of Surgery, Ruhr-University Bochum, Gudrunstr. 56, 44791, Bochum, Germany. · Department of Internal Medicine I, University of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany. thomas.seufferlein@uniklinik-ulm.de. ·BMC Cancer · Pubmed #30594153.

ABSTRACT: BACKGROUND: Even clearly resectable pancreatic cancer still has an unfavorable prognosis. Neoadjuvant or perioperative therapies might improve the prognosis of these patients. Thus, evaluation of perioperative chemotherapy in resectable pancreatic cancer in a prospective, randomized trial is warranted. A substantial improvement in overall survival of patients with metastatic pancreatic cancer with FOLFIRINOX and nab-paclitaxel/gemcitabine vs standard gemcitabine has been demonstrated in phase III-trials. Indeed nab-paclitaxel/gemcitabine has a more favorable toxicity profile compared to the FOLFIRINOX protocol and appears applicable in a perioperative setting. METHODS: NEONAX is an interventional, prospective, randomized, controlled, open label, two sided phase II study with an unconnected analysis of the results in both experimental arms against a fixed survival probability (38% at 18 months with adjuvant gemcitabine), NCT02047513. NEONAX will enroll 166 patients with resectable pancreatic ductal adenocarcinoma (≤ cT3, N0 or N1, cM0) in two arms: Arm A (perioperative arm): 2 cycles nab-paclitaxel (125 mg/m2)/gemcitabine (1000 mg/m2, d1, 8 and 15 of an 28 day-cycle) followed by tumor surgery followed by 4 cycles nab-paclitaxel/gemcitabine, Arm B (adjuvant arm): tumor surgery followed by 6 cycles nab-paclitaxel/gemcitabine. The randomization (1:1) is eminent to avoid allocation bias between the groups. Randomization is stratified for tumor stage (ct1/2 vs. cT3) and lymph node status (cN0 vs. cN1). Primary objective is disease free survival (DFS) at 18 months after randomization. Key secondary objectives are 3-year overall survival (OS) rate and DFS rate, progression during neoadjuvant therapy, R0 and R1 resection rate, quality of life and correlation of DFS, OS and tumor regression with pharmacogenomic markers, tumor biomarkers and molecular analyses (ctDNA, transcriptome, miRNA-arrays). In addition, circulating tumor-DNA will be analyzed in patients with the best and the worst responses to the neoadjuvant treatment. The study was initiated in March 2015 in 26 centers for pancreatic surgery in Germany. DISCUSSION: The NEONAX trial is an innovative study on resectable pancreatic cancer and currently one of the largest trials in this field of research. It addresses the question of the role of intensified perioperative treatment with nab-paclitaxel plus gemcitabine in resectable pancreatic cancers to improve disease-free survival and offers a unique potential for translational research. TRIAL REGISTRATION: ClinicalTrials.gov : NCT02047513, 08/13/2014.

5 Article Inflammation-induced NFATc1-STAT3 transcription complex promotes pancreatic cancer initiation by KrasG12D. 2014

Baumgart, Sandra / Chen, Nai-Ming / Siveke, Jens T / König, Alexander / Zhang, Jin-San / Singh, Shiv K / Wolf, Elmar / Bartkuhn, Marek / Esposito, Irene / Heßmann, Elisabeth / Reinecke, Johanna / Nikorowitsch, Julius / Brunner, Marius / Singh, Garima / Fernandez-Zapico, Martin E / Smyrk, Thomas / Bamlet, William R / Eilers, Martin / Neesse, Albrecht / Gress, Thomas M / Billadeau, Daniel D / Tuveson, David / Urrutia, Raul / Ellenrieder, Volker. ·Authors' Affiliations:Signaling and Transcription Laboratory, Department of Gastroenterology, Philipps University, Marburg; Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen; II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität; Institute of Pathology, Helmholtz Zentrum, Munich; Theodor Boveri Institute, University of Würzburg, Würzburg; Institute for Genetics, Justus-Liebig-University, Giessen, Germany; Schulze Center for Novel Therapeutics, Division of Oncology Research; Divisions of Anatomic Pathology and Biostatistics, College of Medicine; Laboratory of Epigenetics and Chromatin Dynamics, Department of Medicine, Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota; Barrow Brain Tumor Research Center, St. Joseph's Hospital and Medical Center, Phoenix, Arizona; and Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. · Authors' Affiliations:Signaling and Transcription Laboratory, Department of Gastroenterology, Philipps University, Marburg; Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen; II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität; Institute of Pathology, Helmholtz Zentrum, Munich; Theodor Boveri Institute, University of Würzburg, Würzburg; Institute for Genetics, Justus-Liebig-University, Giessen, Germany; Schulze Center for Novel Therapeutics, Division of Oncology Research; Divisions of Anatomic Pathology and Biostatistics, College of Medicine; Laboratory of Epigenetics and Chromatin Dynamics, Department of Medicine, Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota; Barrow Brain Tumor Research Center, St. Joseph's Hospital and Medical Center, Phoenix, Arizona; and Cold Spring Harbor Laboratory, Cold Spring Harbor, New YorkAuthors' Affiliations:Signaling and Transcription Laboratory, Department of Gastroenterology, Philipps University, Marburg; Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen; II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität; Institute of Pathology, Helmholtz Zentrum, Munich; Theodor Boveri Institute, University of Würzburg, Würzburg; Institute for Genetics, Justus-Liebig-University, Giessen, Germany; Schulze Center for Novel Therapeutics, Division of Oncology Research; Divisions of Anatomic Pathology and Biostatistics, College of Medicine; Laboratory of Epigenetics and Chromatin Dynamics, Department of Medicine, Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota; Barrow Brain Tumor Research Center, St. Joseph's Hospital and Medical Center, Phoenix, Arizona; and Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. · Authors' Affiliations:Signaling and Transcription Laboratory, Department of Gastroenterology, Philipps University, Marburg; Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen; II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität; Institute of Pathology, Helmholtz Zentrum, Munich; Theodor Boveri Institute, University of Würzburg, Würzburg; Institute for Genetics, Justus-Liebig-University, Giessen, Germany; Schulze Center for Novel Therapeutics, Division of Oncology Research; Divisions of Anatomic Pathology and Biostatistics, College of Medicine; Laboratory of Epigenetics and Chromatin Dynamics, Department of Medicine, Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota; Barrow Brain Tumor Research Center, St. Joseph's Hospital and Medical Center, Phoenix, Arizona; and Cold Spring Harbor Laboratory, Cold Spring Harbor, New YorkAuthors' Affiliations:Signaling and Transcription Laboratory, Department of Gastroenterology, Philipps University, Marburg; Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen; II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität; Institute of Pathology, Helmholtz Zentrum, Munich; Theodor Boveri Institute, University of Würzburg, Würzburg; Institute for Genetics, Justus-Liebig-University, Giessen, Germany; Schulze Center for Novel Therapeutics, Division of Oncology Research; Divisions of Anatomic Pathology and Biostatistics, College of Medicine; Laboratory of Epigenetics and Chromatin Dynamics, Department of Medicine, Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota; Barrow Brain Tumor Research Center, St. Joseph's Hospital and Medical Center, Phoenix, Arizona; and Cold Spring Harbor Laboratory, Cold Spring Harbor, New YorkAuthors' Affiliations:Signaling and Transcription Laboratory, Department of Gastroenterology, Philipps University, Marburg · Authors' Affiliations:Signaling and Transcription Laboratory, Department of Gastroenterology, Philipps University, Marburg; Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen; II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität; Institute of Pathology, Helmholtz Zentrum, Munich; Theodor Boveri Institute, University of Würzburg, Würzburg; Institute for Genetics, Justus-Liebig-University, Giessen, Germany; Schulze Center for Novel Therapeutics, Division of Oncology Research; Divisions of Anatomic Pathology and Biostatistics, College of Medicine; Laboratory of Epigenetics and Chromatin Dynamics, Department of Medicine, Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota; Barrow Brain Tumor Research Center, St. Joseph's Hospital and Medical Center, Phoenix, Arizona; and Cold Spring Harbor Laboratory, Cold Spring Harbor, New York urrutia.raul@mayo.edu ellenrie@med.uni-marburg.de. ·Cancer Discov · Pubmed #24694735.

ABSTRACT: SIGNIFICANCE: Our study points to the existence of an oncogenic NFATc1-STAT3 cooperativity that mechanistically links inflammation with pancreatic cancer initiation and progression. Because NFATc1-STAT3 nucleoprotein complexes control the expression of gene networks at the intersection of inflammation and cancer, our study has significant relevance for potentially managing pancreatic cancer and other inflammatory-driven malignancies.

6 Article Disruption of a nuclear NFATc2 protein stabilization loop confers breast and pancreatic cancer growth suppression by zoledronic acid. 2011

Singh, Shiv K / Baumgart, Sandra / Singh, Garima / König, Alexander O / Reutlinger, Kristina / Hofbauer, Lorenz C / Barth, Peter / Gress, Thomas M / Lomberk, Gwen / Urrutia, Raul / Fernandez-Zapico, Martin E / Ellenrieder, Volker. ·Signaling and Transcription Laboratory, Department of Gastroenterology, Philipps-University of Marburg, D-35043 Marburg, Germany. ·J Biol Chem · Pubmed #21628454.

ABSTRACT: The aminobisphosphonate zoledronic acid has elicited significant attention due to its remarkable anti-tumoral activity, although its detailed mechanism of action remains unclear. Here, we demonstrate the existence of a nuclear GSK-3β-NFATc2 stabilization pathway that promotes breast and pancreatic cancer growth in vitro and in vivo and serves as a bona fide target of zoledronic acid. Specifically, the serine/threonine kinase GSK-3β stabilizes nuclear NFATc2 through phosphorylation of the serine-rich SP2 domain, thus protecting the transcription factor from E3-ubiquitin ligase HDM2-mediated proteolysis. Zoledronic acid disrupts this NFATc2 stabilization pathway through two mechanisms, namely GSK-3β inhibition and induction of HDM2 activity. Upon nuclear accumulation, HDM2 targets unphosphorylated NFATc2 for ubiquitination at acceptor lysine residues Lys-684/Lys-897 and hence labels the factor for subsequent proteasomal degradation. Conversely, mutagenesis-induced constitutive serine phosphorylation (Ser-215, Ser-219, and Ser-223) of the SP2 domain prevents NFATc2 from HDM2-mediated ubiquitination and degradation and consequently rescues cancer cells from growth suppression by zoledronic acid. In conclusion, this study demonstrates a critical role of the GSK-3β-HDM2 signaling loop in the regulation of NFATc2 protein stability and growth promotion and suggests that double targeting of this pathway is responsible, at least to a significant part, for the potent and reliable anti-tumoral effects of zoledronic acid.