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Pancreatic Neoplasms: HELP
Articles by Patrick Michl
Based on 33 articles published since 2009
(Why 33 articles?)
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Between 2009 and 2019, P. Michl wrote the following 33 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline [S3-guideline exocrine pancreatic cancer]. 2013

Seufferlein, T / Porzner, M / Becker, T / Budach, V / Ceyhan, G / Esposito, I / Fietkau, R / Follmann, M / Friess, H / Galle, P / Geissler, M / Glanemann, M / Gress, T / Heinemann, V / Hohenberger, W / Hopt, U / Izbicki, J / Klar, E / Kleeff, J / Kopp, I / Kullmann, F / Langer, T / Langrehr, J / Lerch, M / Löhr, M / Lüttges, J / Lutz, M / Mayerle, J / Michl, P / Möller, P / Molls, M / Münter, M / Nothacker, M / Oettle, H / Post, S / Reinacher-Schick, A / Röcken, C / Roeb, E / Saeger, H / Schmid, R / Schmiegel, W / Schoenberg, M / Siveke, J / Stuschke, M / Tannapfel, A / Uhl, W / Unverzagt, S / van Oorschot, B / Vashist, Y / Werner, J / Yekebas, E / Anonymous230779 / Anonymous240779 / Anonymous250779. ·Klinik für Innere Medizin I, Universitätsklinikum Ulm. · Klinik für Allgemeine Chirurgie, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Kiel. · Klinik für Radioonkologie und Strahlentherapie, Charité Universitätsmedizin Berlin. · Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar, TU München. · Institut für Allgemeine Pathologie, Klinikum rechts der Isar, TU München. · Strahlenklinik, Universitätsklinikum Erlangen. · Leitlinienprogramm Onkologie, Deutsche Krebsgesellschaft e. V., Berlin. · I. Medizinische Klinik und Poliklinik, Universitätsmedizin Mainz. · Klinik für Allgemeine Innere Medizin, Onkologie/Hämatologie, Gastroenterologie und Infektiologie, Klinikum Esslingen. · Klinik für Allgemeine Chirurgie, Viszeral-, Gefäß- und Kinderchirurgie, Universitätsklinikum des Saarlandes Homburg/Saar. · Klinik für Gastroenterologie, Endokrinologie und Stoffwechsel, Universitätsklinikum Gießen und Marburg. · Medizinischen Klinik und Poliklinik III, Klinikum der Universität München LMU. · Chirurgische Klinik, Universitätsklinikum Erlangen. · Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Freiburg. · Klinik für Allgemein-, Viszeral- und Thoraxchirurgie, Universitätsklinikum Hamburg-Eppendorf. · Klinik für Allgemeine Chirurgie, Thorax-, Gefäß- und Transplantationschirurgie, Universitätsmedizin Rostock. · AWMF-Institut für Medizinisches Wissensmanagement, Marburg. · Medizinische Klinik I, Klinikum Weiden. · Klinik für Allgemein-, Gefäß- und Viszeralchirurgie, Martin-Luther-Krankenhaus Berlin. · Klinik und Poliklinik für Innere Medizin A, Universitätsmedizin Greifswald. · Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm. · Institut für Pathologie, Marienkrankenhaus Hamburg. · Medizinische Klinik - Schwerpunkt Gastroenterologie, Endokrinologie, Infektiologie, Caritasklinikum Saarbrücken. · Institut für Pathologie, Universitätsklinikum Ulm. · Klinik und Poliklinik für Strahlentherapie und Radiologische Onkologie, Klinikum rechts der Isar, TU München. · Klinik für Strahlentherapie und Radioonkologie, Klinikum Stuttgart. · AWMF-Institut für Medizinisches Wissensmanagement, Berlin. · Medizinische Klinik mit Schwerpunkt Hämatologie und Onkologie, Charité Universitätsmedizin Berlin. · Chirurgische Klinik, Universitätsmedizin Mannheim. · Abt. für Hämatologie und Onkologie, St. Josef-Hospital, Klinikum der Ruhr-Universität Bochum. · Institut für Pathologie, Universitätsklinikum Kiel. · Medizinische Klinik II, SP Gastroenterologie, Universitätsklinikum Gießen und Marburg. · Klinik für Viszeral-, Thorax- und Gefäßchirurgie, Universitätsklinikum Dresden. · II. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, TU München. · Medizinische Klinik, Klinikum der Ruhr-Universität Bochum. · Klinik für Chirurgie, Rotkreuzklinikum München. · Klinik für Strahlentherapie, Universitätsklinikum Essen. · Institut für Pathologie, Ruhr-Universität Bochum. · Chirurgische Klinik, St. Josef-Hospital, Klinikum der Ruhr-Universität Bochum. · Institut für Medizinische Epidemiologie, Biometrie und Informatik, Martin-Luther-Universität Halle-Wittenberg. · Klinik und Poliklinik für Strahlentherapie, Universitätsklinikum Würzburg. · Klinik für Allgemeine, Viszerale und Transplantationschirurgie, Universitätsklinikum Heidelberg. · Klinik für Allgemein-, Thorax- und Viszeralchirurgie, Klinikum Darmstadt. ·Z Gastroenterol · Pubmed #24338757.

ABSTRACT: -- No abstract --

2 Guideline New strategies and designs in pancreatic cancer research: consensus guidelines report from a European expert panel. 2012

Van Laethem, J-L / Verslype, C / Iovanna, J L / Michl, P / Conroy, T / Louvet, C / Hammel, P / Mitry, E / Ducreux, M / Maraculla, T / Uhl, W / Van Tienhoven, G / Bachet, J B / Maréchal, R / Hendlisz, A / Bali, M / Demetter, P / Ulrich, F / Aust, D / Luttges, J / Peeters, M / Mauer, M / Roth, A / Neoptolemos, J P / Lutz, M / Anonymous6430701. ·Gastrointestinal Cancer Unit, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium. jl.vanlaethem@erasme.ulb.ac.be ·Ann Oncol · Pubmed #21810728.

ABSTRACT: Although the treatment of pancreatic ductal adenocarcinoma (PDAC) remains a huge challenge, it is entering a new era with the development of new strategies and trial designs. Because there is an increasing number of novel therapeutic agents and potential combinations available to test in patients with PDAC, the identification of robust prognostic and predictive markers and of new targets and relevant pathways is a top priority as well as the design of adequate trials incorporating molecular-driven hypothesis. We presently report a consensus strategy for research in pancreatic cancer that was developed by a multidisciplinary panel of experts from different European institutions and collaborative groups involved in pancreatic cancer. The expert panel embraces the concept of exploratory early proof of concept studies, based on the prediction of response to novel agents and combinations, and randomised phase II studies permitting the selection of the best therapeutic approach to go forward into phase III, where the recommended primary end point remains overall survival. Trials should contain as many translational components as possible, relying on standardised tissue and blood processing and robust biobanking, and including dynamic imaging. Attention should not only be paid to the pancreatic cancer cells but also to microenvironmental factors and stem/stellate cells.

3 Review [Cystic lesions of the pancreas : Differential diagnostics and treatment]. 2019

Rosendahl, J / Michl, P. ·Klinik für Innere Medizin I, Universitätsklinikum Halle (Saale), Ernst-Grube-Str. 40, 06120, Halle (Saale), Deutschland. jonas.rosendahl@uk-halle.de. · Klinik für Innere Medizin I, Universitätsklinikum Halle (Saale), Ernst-Grube-Str. 40, 06120, Halle (Saale), Deutschland. ·Internist (Berl) · Pubmed #30617702.

ABSTRACT: Cystic space-occupying lesions of the pancreas represent incidental findings in most cases. As there is a potential risk of malignant transformation further evaluation of the lesions as well as a follow-up of these patients is usually recommended. Before this work-up is initiated the clinical situation of the patient as a whole and comorbidities, age and personal preferences have to be taken into account. So far there are no biomarkers that reliably predict the risk of malignant transformation. Imaging by magnetic resonance tomography (MRI) in combination with magnetic resonance cholangiopancreatography (MRCP) is more accurate than computed tomography to identify worrisome features. During follow-up, endoscopic ultrasound (EUS) can be used as complementary method to MRI/MRCP. Using contrast enhancement or endoscopic fine needle aspiration (EUS-FNA) may influence the therapeutic strategy in some patients. Whereas for some cystic pancreatic lesions consensus has been reached, varying recommendations exist for intraductal papillary mucinous neoplasms (IPMN). There is consensus that in main-duct as well as in mixed-type IPMN surgery is recommended. The management of branch-duct type IPMN, however, remains controversial. A multidisciplinary expert panel including gastroenterologists, visceral surgeons, radiologists and pathologists is essential to discuss all cases of patients with cystic pancreatic lesions and to guarantee an optimal, patient-centered treatment recommendation.

4 Review Stromal biology and therapy in pancreatic cancer: ready for clinical translation? 2019

Neesse, Albrecht / Bauer, Christian Alexander / Öhlund, Daniel / Lauth, Matthias / Buchholz, Malte / Michl, Patrick / Tuveson, David A / Gress, Thomas M. ·Department of Gastroenterology and Gastrointestinal Oncology, University Medicine Goettingen, Goettingen, Germany. · Department of Gastroenterology, Endocrinology, Metabolism and Infectiology, University Hospital Marburg, UKGM, Philipps University Marburg, Marburg, Germany. · Department of Radiation Sciences, Umeå University, Umeå, Sweden. · Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden. · Department of Medicine, Philipps University, Center for Tumour and Immune Biology, Marburg, Germany. · Department of Internal Medicine I, Martin, Luther University Halle-Wittenberg, Halle, Germany. · Lustgarten Foundation Designated Pancreatic Cancer Research Lab at Cold Spring Harbor Laboratory, New York, USA. ·Gut · Pubmed #30177543.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is notoriously aggressive and hard to treat. The tumour microenvironment (TME) in PDA is highly dynamic and has been found to promote tumour progression, metastasis niche formation and therapeutic resistance. Intensive research of recent years has revealed an incredible heterogeneity and complexity of the different components of the TME, including cancer-associated fibroblasts, immune cells, extracellular matrix components, tumour vessels and nerves. It has been hypothesised that paracrine interactions between neoplastic epithelial cells and TME compartments may result in either tumour-promoting or tumour-restraining consequences. A better preclinical understanding of such complex and dynamic network systems is required to develop more powerful treatment strategies for patients. Scientific activity and the number of compelling findings has virtually exploded during recent years. Here, we provide an update of the most recent findings in this area and discuss their translational and clinical implications for basic scientists and clinicians alike.

5 Review Therapeutic developments in pancreatic cancer: current and future perspectives. 2018

Neoptolemos, John P / Kleeff, Jörg / Michl, Patrick / Costello, Eithne / Greenhalf, William / Palmer, Daniel H. ·Department of General Surgery, University of Heidelberg, Heidelberg, Germany. john.neoptolemos@med.uni-heidelberg.de. · Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany. joerg.kleeff@uk-halle.de. · Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. joerg.kleeff@uk-halle.de. · Department of Internal Medicine I, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany. · Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. ·Nat Rev Gastroenterol Hepatol · Pubmed #29717230.

ABSTRACT: The overall 5-year survival for pancreatic cancer has changed little over the past few decades, and pancreatic cancer is predicted to be the second leading cause of cancer-related mortality in the next decade in Western countries. The past few years, however, have seen improvements in first-line and second-line palliative therapies and considerable progress in increasing survival with adjuvant treatment. The use of biomarkers to help define treatment and the potential of neoadjuvant therapies also offer opportunities to improve outcomes. This Review brings together information on achievements to date, what is working currently and where successes are likely to be achieved in the future. Furthermore, we address the questions of how we should approach the development of pancreatic cancer treatments, including those for patients with metastatic, locally advanced and borderline resectable pancreatic cancer, as well as for patients with resected tumours. In addition to embracing newer strategies comprising genomics, stromal therapies and immunotherapies, conventional approaches using chemotherapy and radiotherapy still offer considerable prospects for greater traction and synergy with evolving concepts.

6 Review [Metabolic disorders as paraneoplastic syndromes]. 2018

Krug, S / Michl, P. ·Klinik für Innere Medizin I, Martin-Luther-Universität Halle/Wittenberg, Ernst-Grube-Str. 40, 06114, Halle (Saale), Deutschland. · Klinik für Innere Medizin I, Martin-Luther-Universität Halle/Wittenberg, Ernst-Grube-Str. 40, 06114, Halle (Saale), Deutschland. patrick.michl@uk-halle.de. ·Internist (Berl) · Pubmed #29181551.

ABSTRACT: Paraneoplastic syndromes are characterized by the tumor-induced release of peptide hormones and/or the initiation of immune phenomena, which elicit clinical changes and alterations in laboratory parameters independent of the tumor size and spread. In addition to neurological, endocrinal and rheumatological phenotypes, metabolic alterations play a special role in the clinical routine as they commonly present with acute symptoms in an emergency situation and necessitate immediate diagnosis and prompt initiation of treatment. Metabolic alterations within the framework of malignant diseases should be treated in a multidisciplinary team and it is often necessary to perform monitoring and treatment in an intensive care unit. This article focuses on the diagnostic and therapeutic options for metabolic disorders due to paraneoplastic syndromes, such as hypercalcemia, hypocalcemia, hyperglycemia, hypoglycemia and a special variant of tumor-induced metabolic disorders due to tumor lysis syndrome.

7 Review The Role of Cytotoxic Chemotherapy in Advanced Pancreatic Neuroendocrine Tumors. 2017

Krug, Sebastian / Gress, Thomas M / Michl, Patrick / Rinke, Anja. ·Department of Internal Medicine I, Martin-Luther University Halle/Wittenberg, Halle, Germany. ·Digestion · Pubmed #28728148.

ABSTRACT: BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) are rare neoplasms accounting for less than 5% of all pancreatic malignancies. These tumors are characterized by clinical and prognostical heterogeneity and are predominantly diagnosed in a metastatic stage. Cytotoxic chemotherapy, along with alkylating agents and antimetabolites as well as molecular targeted agents (everolimus, sunitinib), is used in the treatment of advanced PNETs. After the approval of lanreotide for unresectable PNETs, an additional therapeutic option has become available; however, the best sequence of therapies and patient stratification to different treatments remains challenging. Furthermore, no randomized phase-3 trials or head-to-head comparisons are available to support treatment decisions. SUMMARY: The publication of 3 large single-center retrospective studies on streptozocin-(STZ)-based chemotherapy in advanced PNETs in 2015 confirmed the effectiveness of this treatment as described in previously reported trials. All studies investigated markers for progression-free and overall survival and strongly supported the value of the Ki-67 index as a robust prognostic marker. Interestingly, chemotherapy consistently displayed antitumor efficacy in different therapeutic lines. Moreover, a recent study of dacarbazine (DTIC) in a cohort of patients predominantly with PNETs demonstrated that a once monthly infusional DTIC schedule was well tolerated and yielded similar response rates (RR) as STZ-based schedules. Given the overall good tolerability of a monthly infusion and RR similar to STZ schedules, DTIC thus represents a feasible alternative or additional treatment option for PNETs. In this article, we review the current standard and summarize the most recent advances in the field of cytotoxic chemotherapy for PNET patients. Key Messages: (1) Despite the lack of phase3 trials, cytotoxic chemotherapy offers efficacy for patients with advanced PNETs; (2) the best therapeutic option and sequence remain open since comparable randomized studies are lacking; (3) careful patient selection and treatment stratification may increase overall outcome; and (4) currently, no biomarkers for clinical routine exist to predict response to chemotherapy.

8 Review nab-Paclitaxel: novel clinical and experimental evidence in pancreatic cancer. 2014

Neesse, A / Michl, P / Tuveson, D A / Ellenrieder, V. ·Department of Gastroenterology, Endocrinology, Infectiology and Metabolism, Philipps University Marburg, Marburg, Germany. · Cold Spring Harbor, Laboratory Cold Spring Harbor, NY, USA. ·Z Gastroenterol · Pubmed #24687799.

ABSTRACT: The past few decades have seen virtually no treatment advances for patients with metastatic pancreatic cancer. Clinical hallmark features of pancreatic ductal adenocarcinoma (PDA) include late symptom onset, invasive growth, early liver and lymph node metastasis, and resistance to available chemotherapies. nab-Paclitaxel (Abraxane®) is generated through high-pressure homogenization of human albumin and conventional paclitaxel resulting in non-covalently bound, water-soluble albumin-paclitaxel particles with an approximate diameter of 130 nm. Results from the recently completed Metastatic Pancreatic Adenocarcinoma Trial (MPACT) (phase III trial) showed a significant survival benefit for patients treated with nab-paclitaxel in combination with gemcitabine, and this treatment regimen is currently being implemented in national and international guidelines for PDA patients. Therefore, this regimen provides a much needed vantage point of attack for this recalcitrant tumor offering potential new hope for our patients. Mechanisms such as stromal depletion, selective intratumoral accumulation, synergism with gemcitabine metabolism and secreted protein acidic and rich in cysteine (SPARC) mediated anti-tumor activity have been suggested for nab-paclitaxel. This review discusses the clinical and experimental advances of nab-paclitaxel in pancreatic cancer.

9 Review Current concepts and novel targets in advanced pancreatic cancer. 2013

Michl, Patrick / Gress, Thomas M. ·Department of Gastroenterology, Endocrinology and Metabolism, Philipps University Marburg, Baldinger Strasse, Marburg 35043, Germany. ·Gut · Pubmed #23112132.

ABSTRACT: Pancreatic cancer remains one of the most aggressive tumours with a 5-year survival rate of less than 5%. The dismal prognosis of this tumour entity that is associated with a high degree of drug resistance has not changed over the past decades. Since 1997, gemcitabine-based regimens have been the therapy of choice for advanced pancreatic cancer. Recently, however, new combination chemotherapy regimens achieved a significant survival benefit compared to gemcitabine-based therapies. In addition, novel approaches to improve drug delivery are currently being developed, and new drugs targeting signalling pathways both within the tumour cells and the tumour microenvironment are undergoing preclinical and clinical validation. Furthermore, efforts are being made to identify predictive markers for individualised treatment approaches based on molecular tumour characteristics. This review provides an overview on current and emerging concepts as well as novel targets for systemic treatment of advanced pancreatic cancer. Combination therapies incorporating drugs directed against these new targets may open new avenues for improving the efficacy of current treatment approaches and overcoming the devastating prognosis of pancreatic cancer patients.

10 Review New developments in pancreatic cancer treatment. 2012

Krug, S / Michl, P. ·Department of Gastroenterology, Endocrinology and Metabolism, Philipps University Marburg, Marburg, Germany. ·Minerva Gastroenterol Dietol · Pubmed #23207616.

ABSTRACT: Pancreatic ductal adenocarcinomas belong to the most aggressive solid malignancies. The devastating prognosis of this tumor entity is associated with a high degree of resistance to systemic therapy approaches. Although new combination chemotherapy regimens have recently demonstrated a significant survival benefit compared to gemcitabine-based therapies, the search for novel treatment options still remains a huge challenge. After numerous potential targets have proven to be futile in clinical trials, recent efforts have been made to both improve drug delivery and to identify drugs targeting novel signalling pathways within the tumors including the putative stem cell compartment and the tumor stroma. Furthermore, predictive markers are needed to define tailored treatment regimens according to the molecular profile of individual tumors. In this review, current therapeutic strategies as well as emerging avenues for systemic therapy and response prediction for individualized therapy of pancreatic cancer patients are discussed which are currently evaluated to overcome the highly drug-resistant phenotype of this malignancy.

11 Review Claudin-4 as therapeutic target in cancer. 2012

Neesse, A / Griesmann, H / Gress, T M / Michl, P. ·Department of Gastroenterology, Endocrinology and Metabolism, Philipps University Marburg, Baldinger Str., 35043 Marburg, Germany. ·Arch Biochem Biophys · Pubmed #22286027.

ABSTRACT: BACKGROUND: Intercellular junctional complexes such as adherens junctions and tight junctions are critical regulators of cellular polarity, paracellular permeability and metabolic and structural integrity of cellular networks. Abundant expression analysis data have yielded insights into the complex pattern of differentially expressed cell-adhesion proteins in epithelial cancers and provide a useful platform for functional, preclinical and clinical evaluation of novel targets. SCOPE OF REVIEW: This review will focus on the role of claudin-4, an integral constituent of tight junctions, in the pathophysiology of epithelial malignancies with particular focus pancreatic cancer, and its potential applicability for prognostic, diagnostic and therapeutic approaches. MAJOR CONCLUSIONS: Claudin-4 expression is widely dysregulated in epithelial malignancies and in a number of premalignant precursor lesions. Although the functional implications are only starting to unravel, claudin-4 seems to play an important role in tumour cell invasion and metastasis, and its dual role as receptor of Clostridium perfringens enterotoxin (CPE) opens exciting avenues for molecular targeted approaches. GENERAL SIGNIFICANCE: Claudin-4 constitutes a promising molecular marker for prognosis, diagnosis and therapy of epithelial malignancies.

12 Review Therapeutic targeting of apoptotic pathways: novel aspects in pancreatic cancer. 2012

Neesse, A / Gress, T M / Michl, P. ·Division of Gastroenterology, Endocrinology and Metabolism, Philipps University Marburg, Baldinger Strasse, Marburg, Germany. ·Curr Pharm Biotechnol · Pubmed #21605073.

ABSTRACT: Pancreatic cancer constitutes one of the most aggressive tumours with a 5-year survival rate of less than 5%. It is characterized by a high degree of resistance to apoptosis which is associated by high expression levels of multiple prosurvival proteins of the extrinsic and intrinsic apoptosis signalling cascades. This review focuses on current knowledge of apoptotic pathways involved in pancreatic cancer and mechanisms of resistance to apoptosis, including alterations in the death receptor and mitochondrial pathways, as well as anti-apoptotic effects of NF-kB and Akt signalling and the impact of histone-modifying enzymes such as histondeacetylases (HDAC). Furthermore, the therapeutic implications of modulating pro-survival pathways by specific inhibitors investigated in preclinical and clinical trials will be discussed.

13 Review Stromal biology and therapy in pancreatic cancer. 2011

Neesse, Albrecht / Michl, Patrick / Frese, Kristopher K / Feig, Christine / Cook, Natalie / Jacobetz, Mike A / Lolkema, Martijn P / Buchholz, Malte / Olive, Kenneth P / Gress, Thomas M / Tuveson, David A. ·Li Ka Shing Centre, Cambridge Research Institute, Cancer Research UK, Cambridge, UK. ·Gut · Pubmed #20966025.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is an almost uniformly lethal disease. One explanation for the devastating prognosis is the failure of many chemotherapies, including the current standard of care therapy gemcitabine. Although our knowledge of the molecular events underlying multistep carcinogenesis in PDA has steadily increased, translation into more effective therapeutic approaches has been inefficient over the last several decades. Evidence for this innate resistance to systemic therapies was recently provided in an accurate mouse model of PDA by the demonstration that chemotherapies are poorly delivered to PDA tissues because of a deficient vasculature. This vascular deficiency correlated with the presence of a dense stromal matrix that is a prominent histological hallmark of PDA tumours. Therapeutic targeting of stromal cells decreased the stroma from pancreatic tumours, resulting in increased intratumoral perfusion and therapeutic delivery of gemcitabine. Stromal cells contained within the PDA tumour microenvironment therefore represent an additional constituent to neoplastic cells that should be critically evaluated for optimal therapeutic development in preclinical models and early clinical trials.

14 Clinical Trial Phase I/II Study of Refametinib (BAY 86-9766) in Combination with Gemcitabine in Advanced Pancreatic cancer. 2017

Van Laethem, Jean-Luc / Riess, Hanno / Jassem, Jacek / Haas, Michael / Martens, Uwe M / Weekes, Colin / Peeters, Marc / Ross, Paul / Bridgewater, John / Melichar, Bohuslav / Cascinu, Stefano / Saramak, Piotr / Michl, Patrick / Van Brummelen, David / Zaniboni, Alberto / Schmiegel, Wollf / Dueland, Svein / Giurescu, Marius / Garosi, Vittorio L / Roth, Katrin / Schulz, Anke / Seidel, Henrik / Rajagopalan, Prabhu / Teufel, Michael / Childs, Barrett H. ·Department of Gastroenterology, Erasme University Hospital, CP 572/10, route de Lennik 808, 1070, Brussels, Belgium. JL.VanLaethem@erasme.ulb.ac.be. · Medical Department, Division of Hematology, Oncology and Tumor Immunology, Charity Hospital, Virchow-Klinikum Campus, Augustenburger Platz 1, 13353, Berlin, Germany. · Department of Oncology and Radiotherapy, Medical University of Gdansk, M. Skłodowskiej-Curie 3a Street, Gdansk, 80-210, Poland. · Department of Hematology and Oncology, University of Munich Medical Center, Marchioninistraße 15, 81366, Munich, Germany. · Department of Hematology and Oncology, Cancer Center Heilbronn-Franken, Am Gesundbrunnen 20-26, 74078, Heilbronn, Germany. · Division of Medical Oncology, University of Colorado Cancer Center, 1665 Aurora Ct, Aurora, CO, 80045, USA. · Department of Oncology, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Belgium. · Department of Medical Oncology, Guy's & St Thomas' Hospital, Westminster Bridge Road, London, SE1 7EH, UK. · Department of Oncology, UCL Cancer Institute, 72 Huntley Street, London, WC1E 6DD, UK. · Department of Oncology, Palacky University Medical School and University Hospital Olomouc, Křížkovského 8, 771 47, Olomouc, Czech Republic. · Department of Medical Oncology, A.O.U. United Hospitals, Polytechnic University of Marche, Piazza Roma, 22, Ancona, Italy. · Department of Oncological Gastroenterology, Maria Skłodowska-Curie Memorial Cancer Center, ul. W.K. Roentgena 5, 02-781, Warsaw, Poland. · Department of Gastroenterology, Endocrinology, Metabolism and Infectiology, University Hospital of Giessen and Marburg, Baldingerstraße, 35043, Marburg, Germany. · Universitätsklinikum Halle - University Hospital Halle (Saale), Ernst-Grube-Straße 40, 06120, Halle (Saale), Germany. · Department of Radiotherapy, UZ Brussels, Avenue du Laerbeek 101, 1090, Brussels, Belgium. · Department of Medical Oncology, Poliambulanza Foundation Hospital Institute, Via Bissolati, 57, Brescia, Italy. · Department of Gastroenterology and Hepatology, Medical University Hospital Bochum, Alexandrinenstraße 1, Bochum, 44791, Germany. · Department of Oncology, Oslo University Radium Hospital, Trondheimsveien 235, Bjerke, 0514, Oslo, Norway. · Bayer Pharma AG, Müllerstraße 178, 13353, Berlin, Germany. · Bayer S.p.A., Viale Certosa 126-130, 20156, Milan, Italy. · Bayer HealthCare Pharmaceuticals, Inc., 100 Bayer Blvd, Whippany, NJ, 07981, USA. ·Target Oncol · Pubmed #27975152.

ABSTRACT: BACKGROUND: Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently inhibits MEK1/2, part of the MAPK signaling pathway. This phase I/II study evaluated the safety and efficacy of refametinib plus gemcitabine in patients with advanced pancreatic cancer. METHODS: Phase I comprised dose escalation, followed by phase II expansion. Refametinib and gemcitabine plasma levels were analyzed for pharmacokinetics. KRAS mutational status was determined from circulating tumor DNA. RESULTS: Ninety patients overall received treatment. The maximum tolerated dose was refametinib 50 mg twice daily plus standard gemcitabine (1000 mg/m CONCLUSION: Refametinib plus gemcitabine was well tolerated, with a promising objective response rate, and had an acceptable safety profile and no pharmacokinetic interaction. There was a trend towards improved outcomes in patients without detectable KRAS mutations that deserves future investigation.

15 Clinical Trial DocOx (AIO-PK0106): a phase II trial of docetaxel and oxaliplatin as a second line systemic therapy in patients with advanced pancreatic ductal adenocarcinoma. 2016

Ettrich, Thomas J / Perkhofer, Lukas / von Wichert, Goetz / Gress, Thomas M / Michl, Patrick / Hebart, Holger F / Büchner-Steudel, Petra / Geissler, Michael / Muche, Rainer / Danner, Bettina / Kächele, Volker / Berger, Andreas W / Güthle, Melanie / Seufferlein, Thomas. ·Department of Internal Medicine, Schön-Klinik Hamburg-Eilbeck, Hamburg, Germany. goetz.wichert@gmx.de. · Department of Gastroenterology, Endocrinology, Metabolism and Infectiology, Philipps University of Marburg, Marburg, Germany. gress@med.uni-marburg.de. · Department of Internal Medicine I, Martin-Luther-University, Halle (Saale), Germany. patrick.michl@uk-halle.de. · Department of Internal Medicine, Stauferklinikum Schwaebisch-Gmuend, Mutlangen, Germany. holger.hebart@stauferklinikum.de. · Department of Internal Medicine I, Martin-Luther-University, Halle (Saale), Germany. petra.buechner-steudel@uk-halle.de. · Department of Internal Medicine, Oncology/Hematology, Gastroenterology, Esslingen Hospital, Esslingen, Germany. m.geissler@klinikum-esslingen.de. · Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany. rainer.muche@uni-ulm.de. · Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany. bettina.danner@uni-ulm.de. · Praxis für Hämatologie und Onkologie Ulm, Ulm, Germany. volker.kaechele@gmx.de. · Department of Internal Medicine I, Ulm University, Albert-Einstein-Allee 23, D-89081, Ulm, Germany. andreas.berger@uniklinik-ulm.de. · Department of Internal Medicine I, Ulm University, Albert-Einstein-Allee 23, D-89081, Ulm, Germany. melanie.guethle@uniklinik-ulm.de. · Department of Internal Medicine I, Ulm University, Albert-Einstein-Allee 23, D-89081, Ulm, Germany. thomas.seufferlein@uniklinik-ulm.de. ·BMC Cancer · Pubmed #26772812.

ABSTRACT: BACKGROUND: The current study was conducted to examine the activity of a docetaxel/oxaliplatin (DocOx) combination as second line treatment for advanced pancreatic ductal adenocarcinoma (Trial registration: NCT00690300. Registered June 2, 2008) METHODS: DocOx is a prospective, multi-center, single arm, phase II trial using docetaxel (75 mg/m(2), 60 min, d 1) and oxaliplatin (80 mg/m(2), 120 min, d 2) in 21-day cycles. The treatment period was scheduled for up to 8 cycles. Primary endpoint was tumor response according to RECIST 1.0. Secondary endpoints were progression free survival, overall survival, safety/toxicity, quality of life and clinical benefit. RESULTS: Data represent the intention to treat analysis of 44 patients with chemorefractory pancreatic cancer enrolled between 2008 and 2012 at five institutions in Germany. The primary endpoint of tumor response was achieved in 15.9% of the patients (7 partial remissions, no complete remission), with a disease control rate of 48% after the first two treatment cycles. Median progression free survival (PFS) was 1.82 months (CI 95% 1.5-3.96 months) and median overall survival (OS) was 10.1 months (CI 95% 5.1-14.1 months). CONCLUSIONS: This single-arm trial demonstrates that the combination of docetaxel and oxaliplatin yields promising results for the treatment of advanced pancreatic ductal adenocarcinoma patients. Selected patients had particular benefit from this treatment as indicated by long PFS and OS times. Even after 8 cycles of treatment with DocOx a partial response was observed in 2 patients and stable disease was observed in another 6 patients. The data obtained with the DocOx protocol compare well with other second line protocols such as OFF (oxaliplatin, 5-FU, leucovorin). The DocOx regimen could be an interesting option for patients who received gemcitabine as first line treatment for metastatic pancreatic cancer.

16 Clinical Trial Multicenter phase II trial to investigate safety and efficacy of gemcitabine combined with cetuximab as adjuvant therapy in pancreatic cancer (ATIP). 2013

Fensterer, H / Schade-Brittinger, C / Müller, H-H / Tebbe, S / Fass, J / Lindig, U / Settmacher, U / Schmidt, W E / Märten, A / Ebert, M P / Kornmann, M / Hofheinz, R / Endlicher, E / Brendel, C / Barth, P J / Bartsch, D K / Michl, P / Gress, T M / Anonymous2190765. ·Department of Gastroenterology. ·Ann Oncol · Pubmed #23897705.

ABSTRACT: BACKGROUND: To investigate whether addition of cetuximab to standard adjuvant chemotherapy with gemcitabine improves outcome in pancreatic cancer, specifically whether the rate of disease-free survival (DFS) at 18 months (primary end point) exceeds the previously reported 35% of gemcitabine alone. PATIENTS AND METHODS: Prospective, open-label, multicenter, nonrandomized phase II study in 76 patients with R0- or R1-resected ductal adenocarcinoma of the pancreas included between October 2006 and November 2008. Gemcitabine and cetuximab were administered for 24 weeks. Secondary end points included overall survival (OS) and toxic effect. RESULTS: Seventy-three patients received cetuximab. Median DFS was 10.0 [95% confidence interval (CI) 8.9-13.6] months and the DFS rate at month 18 of 27.1% (16.7%-37.6%) was inferior to 35%. Median OS was 22.4 (18.2-27.9) months. Subgroup analyses revealed a nonsignificant increase in DFS for patients with versus without skin toxic effect ≥ grade 2 (median 14.7 versus 8.3 months, P = 0.073) and wild-type versus mutated K-Ras (median 11.5 versus 9.3 months, P = 0.57). Grade 3/4 toxic effects included neutropenia (11.0%), thrombopenia (7%), skin toxic effect (7%) and allergic reactions (7%). CONCLUSION: Addition of cetuximab to adjuvant gemcitabine does not seem to improve DFS or OS of unstratified pancreatic cancer patients. Trends for improved DFS in patients with wild-type K-Ras and skin toxic effect remain to be confirmed.

17 Article Therapeutic targeting of tumor-associated macrophages in pancreatic neuroendocrine tumors. 2018

Krug, Sebastian / Abbassi, Rami / Griesmann, Heidi / Sipos, Bence / Wiese, Dominik / Rexin, Peter / Blank, Annika / Perren, Aurel / Haybaeck, Johannes / Hüttelmaier, Stefan / Rinke, Anja / Gress, Thomas M / Michl, Patrick. ·Department of Internal Medicine I, Martin Luther University Halle-Wittenberg, Halle, Saale, Germany. · Department of Gastroenterology and Endocrinology, Philipps-University, Marburg, Germany. · Institute of Pathology and Neuropathology, University Hospital of Tübingen, Tübingen, Germany. · Department of Visceral, Thoracic and Vascular Surgery, Philipps-University, Marburg, Germany. · Institute of Pathology, Philipps-University, Marburg, Germany. · Institute of Pathology, University of Bern, Bern, Switzerland. · Department of Pathology, Otto-von-Guericke-University, Magdeburg, Germany. · Institute of Molecular Medicine, Martin Luther University Halle-Wittenberg, Halle, Saale, Germany. ·Int J Cancer · Pubmed #29696624.

ABSTRACT: Pancreatic neuroendocrine tumors (PNETs) represent a heterogeneous group of neuroendocrine neoplasms with varying biological behavior and response to treatment. Although targeted therapies have been shown to improve the survival for patients at advanced stage, resistance to current therapies frequently occurs during the course of therapy. Previous reports indicate that the infiltration of tumor-associated macrophages (TAMs) in PNETs might correlate with tumor progression and metastasis formation. We aimed to evaluate the prognostic and functional impact of TAMs in human PNETs in vitro and in vivo and to investigate the effect of therapeutic targeting TAMs in a genetic PNET mouse model. TAM expression pattern was assessed immunohistochemically in human PNET tissue sections and a tissue-micro-array of PNET tumors with different functionality, stage, and grading. The effect of liposomal clodronate on TAM cell viability was analyzed in myeloid cell lines and isolated murine bone macrophages (mBMM). In vivo, RIP1Tag2 mice developing insulinomas were treated with liposomal clodronate or PBS-Liposomes. Tumor progression, angiogenesis and immune cell infiltration were assessed by immunohistochemistry. In human, insulinomas TAM density was correlated with invasiveness and malignant behavior. Moreover, TAM infiltration in liver metastases was significantly increased compared to primary tumors. In vitro, Liposomal clodronate selectively inhibited the viability of myeloid cells and murine bone macrophages, leaving PNET tumor cell lines largely unaffected. In vivo, repeated application of liposomal clodronate to RIP1Tag2 mice significantly diminished the malignant transformation of insulinomas, which was accompanied by a reduced infiltration of F4/80-positive TAM cells and simultaneously by a decreased microvessel density, suggesting a pronounced effect of clodronate-induced myeloid depletion on tumor angiogenesis. Concomitant treatment with the antiangiogenic TKI sunitinib, however, did not show any synergistic effects with liposomal clodronate. TAMs are crucial for malignant transformation in human PNET and correlate with metastatic behavior. Pharmacological targeting of TAMs via liposomal clodronate disrupts tumor progression in the RIP1Tag2 neuroendocrine tumor model and was associated with reduced tumor angiogenesis. Based on these results, using liposomal clodronate to target proangiogenic myeloid cells could be employed as novel therapeutic avenue in highly angiogenic tumors such as PNET.

18 Article Overcoming immune evasion in pancreatic cancer: the combination matters. 2018

Michl, Patrick / Krug, Sebastian. ·Department of Internal Medicine I, Martin-Luther-University Halle-Wittenberg, Halle, Germany. ·Gut · Pubmed #29217750.

ABSTRACT: -- No abstract --

19 Article Targeted therapy of pancreatic cancer: biomarkers are needed. 2017

Kleeff, Jörg / Michl, Patrick. ·Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther University Halle-Wittenberg, 06120 Halle, Germany. Electronic address: joerg.kleeff@uk-halle.de. · Department of Internal Medicine, Martin-Luther University Halle-Wittenberg, 06120 Halle, Germany. ·Lancet Oncol · Pubmed #28259609.

ABSTRACT: -- No abstract --

20 Article Relevance of dihydropyrimidine-dehydrogenase and thymidylate-synthase in patients with pancreatic neuroendocrine neoplasms treated with 5-FU-based chemotherapy. 2017

Krug, S / Boch, M / Nimphius, W / Gress, T M / Michl, P / Rinke, A. ·Department of Internal Medicine I, Martin Luther University, Halle (Saale), Germany; Department of Gastroenterology and Endocrinology, Philipps-University, Marburg, Germany. · Institute of Pathology, Philipps-University, Marburg, Germany. · Department of Gastroenterology and Endocrinology, Philipps-University, Marburg, Germany. · Department of Internal Medicine I, Martin Luther University, Halle (Saale), Germany. Electronic address: patrick.michl@uk-halle.de. ·Pancreatology · Pubmed #28027897.

ABSTRACT: BACKGROUND: Chemotherapy with 5-FU and Streptozotocin (STZ) is recommended as first-line treatment in patients with metastatic pancreatic neuroendocrine neoplasms (PNEN). However, data about biomarkers involved in the 5-FU metabolism to predict response are still limited. OBJECTIVES: Evaluation of clinicopathological features and potential predictive and prognostic markers of patients with PNEN treated with 5-FU based regimens. PATIENTS AND METHODS: We retrospectively analyzed 41 patients with PNEN who were treated at the University Hospital Marburg between 2000 and 2013. Dihydropyrimidine-Dehydrogenase (DPD) and Thymidylate-Synthase (TS) expression was correlated with treatment response in 19 patients who had available tumour tissue and response data. The median overall survival (OS) and progression free survival (PFS) were calculated using Kaplan-Meier and Cox regression methods, respectively. RESULTS: The median PFS in patients receiving 5-FU/STZ was 17 months with a median OS of 50 months. Objective response rate (ORR) and disease control rate (DCR) were 32% and 73%, respectively. Biochemical response (p = 0.005) and high DPD expression (p = 0.018) were predictive markers of response to 5-FU-based chemotherapy. Univariate analysis identified Ki-67 > 10%, no biochemical response, positive 5-HIAA levels and TS deficiency as independent risk factors for shorter PFS. Moreover, performance status (PS) ≥1 was an independent risk factors for impaired OS. CONCLUSIONS: DPD expression and biochemical response represent promising predictive biomarkers for response to 5-FU based chemotherapy. Moreover, Ki-67, PS and TS are independent prognostic markers of OS and PFS in patients with PNEN.

21 Article Pharmacological macrophage inhibition decreases metastasis formation in a genetic model of pancreatic cancer. 2017

Griesmann, Heidi / Drexel, Christof / Milosevic, Nada / Sipos, Bence / Rosendahl, Jonas / Gress, Thomas M / Michl, Patrick. ·Department of Internal Medicine I, Martin Luther University, Halle, Germany. · Department of Gastroenterology and Endocrinology, Philipps University, Marburg, Germany. · Department of Pathology and Neuropathology, University Hospital Tübingen, Tübingen, Germany. ·Gut · Pubmed #27013602.

ABSTRACT: OBJECTIVES: Tumour-associated macrophages play an important role in mediating tumour progression. In pancreatic cancer, infiltrating macrophages are known to mediate tumour progression and have been identified in invasive tumours and in early preinvasive pancreatic intraepithelial precursor lesions. We aimed to study the impact of pharmacological macrophage depletion by liposomal clodronate in a genetic mouse model of pancreatic cancer. METHODS: KPC mice ( RESULTS: Treatment with liposomal clodronate effectively reduced CD11b-positive macrophages both in the pancreas and other organs such as liver, lung and spleen. While tumour incidence and growth were only slightly reduced, metastasis formation in the liver and lungs was significantly diminished after macrophage depletion. This antimetastatic effect was independent of the presence of an endogenous primary tumour, since reduced pulmonary colonisation was also detected in clodronate-pretreated mice after tail vein injection of syngeneic pancreatic cancer cell lines. Macrophage inhibition by liposomal clodronate was associated with significantly impaired angiogenesis, reduced circulating vascular endothelial growth factor levels and decreased circulating CD4+CD25+ T cells. These alterations could be confirmed in an independent macrophage depletion model using CD11b-diphtheria toxin receptor mice. CONCLUSIONS: Pharmacological depletion of macrophages in a genetic mouse model of pancreatic cancer markedly reduced metastasis formation and is associated with impaired angiogenesis and reduced CD4+CD25+ T cell levels. Pharmacological targeting of infiltrating macrophages represents a promising novel tool for antimetastatic therapeutic approaches.

22 Article CUX1 modulates polarization of tumor-associated macrophages by antagonizing NF-κB signaling. 2015

Kühnemuth, B / Mühlberg, L / Schipper, M / Griesmann, H / Neesse, A / Milosevic, N / Wissniowski, T / Buchholz, M / Gress, T M / Michl, P. ·Department of Gastroenterology and Endocrinology, University Hospital, Philipps University, Marburg, Germany. · Department of Biology, Philipps University, School of Medicine, Marburg, Germany. ·Oncogene · Pubmed #24336331.

ABSTRACT: Many solid cancers including pancreatic ductal adenocarcinoma (PDAC) are characterized by an extensive stromal reaction that is accompanied by infiltrating tumor-associated macrophages (TAMs). The role of TAMs in malignant tumors is only partially understood. Previously, we identified the transcription factor CUX1 as an important mediator of tumor progression in PDAC. Interestingly, we found that CUX1 is highly expressed not only in tumor cells but also in TAMs. On the basis of these data, we aimed to elucidate the effects of CUX1 in TAMs in vitro and in vivo. We analyzed the effects of CUX1 on cytokine expression using overexpression and knockdown strategies. The cytokine regulation by CUX1 was further assessed by reporter assays, DNA pulldown experiments and chromatin-immunoprecipitation. CUX1 expression in TAMs was analyzed in human pancreatic cancer tissues and in a genetic mouse model. Immunohistochemical analysis revealed strong expression levels of CUX1 in a distinct subset of TAMs in human PDAC tissues. Furthermore, its expression increased during tumor progression in a genetic mouse model of PDAC. Profiling experiments showed that CUX1 downregulates several NF-κB-regulated chemokines such as CXCL10, which have been associated with M1 polarization and inhibition of angiogenesis and tumor progression. We could demonstrate that CUX1 interacts with NF-κB p65, leading to reduced binding of NF-κB p65 to the chemokine promoters. In addition, CUX1 reduces acetylation of NF-κB p65 at K310 by recruiting HDAC1. Functionally, CUX1 expression in TAMs antagonizes T-cell attraction and enhances angiogenesis in vitro. We identified CUX1 as an important modulator of the TAMs phenotype and function by modulating NF-κB-dependent cytokines.

23 Article CUX1: a modulator of tumour aggressiveness in pancreatic neuroendocrine neoplasms. 2014

Krug, Sebastian / Kühnemuth, Benjamin / Griesmann, Heidi / Neesse, Albrecht / Mühlberg, Leonie / Boch, Michael / Kortenhaus, Juliane / Fendrich, Volker / Wiese, Dominik / Sipos, Bence / Friemel, Juliane / Gress, Thomas M / Michl, Patrick. ·Departments of GastroenterologyEndocrinology and MetabolismSurgeryPhilipps-University Marburg, Baldingerstraße, 35043 Marburg, GermanyDepartment of PathologyEberhard-Karls-University Tübingen, Tübingen, GermanyDepartment of PathologyUniversity Hospital Zurich, Zurich, Switzerland. · Departments of GastroenterologyEndocrinology and MetabolismSurgeryPhilipps-University Marburg, Baldingerstraße, 35043 Marburg, GermanyDepartment of PathologyEberhard-Karls-University Tübingen, Tübingen, GermanyDepartment of PathologyUniversity Hospital Zurich, Zurich, Switzerland michlp@med.uni-marburg.de. ·Endocr Relat Cancer · Pubmed #25248790.

ABSTRACT: Pancreatic neuroendocrine neoplasms (PNENs) constitute a rare tumour entity, and prognosis and treatment options depend on tumour-mediating hallmarks such as angiogenesis, proliferation rate and resistance to apoptosis. The molecular pathways that determine the malignant phenotype are still insufficiently understood and this has limited the use of effective combination therapies in the past. In this study, we aimed to characterise the effect of the oncogenic transcription factor Cut homeobox 1 (CUX1) on proliferation, resistance to apoptosis and angiogenesis in murine and human PNENs. The expression and function of CUX1 were analysed using knockdown and overexpression strategies in Ins-1 and Bon-1 cells, xenograft models and a genetically engineered mouse model of insulinoma (RIP1Tag2). Regulation of angiogenesis was assessed using RNA profiling and functional tube-formation assays in HMEC-1 cells. Finally, CUX1 expression was assessed in a tissue microarray of 59 human insulinomas and correlated with clinicopathological data. CUX1 expression was upregulated during tumour progression in a time- and stage-dependent manner in the RIP1Tag2 model, and associated with pro-invasive and metastatic features of human insulinomas. Endogenous and recombinant CUX1 expression increased tumour cell proliferation, tumour growth, resistance to apoptosis, and angiogenesis in vitro and in vivo. Mechanistically, the pro-angiogenic effect of CUX1 was mediated via upregulation of effectors such as HIF1α and MMP9. CUX1 mediates an invasive pro-angiogenic phenotype and is associated with malignant behaviour in human insulinomas.

24 Article Nicotine promotes initiation and progression of KRAS-induced pancreatic cancer via Gata6-dependent dedifferentiation of acinar cells in mice. 2014

Hermann, Patrick C / Sancho, Patricia / Cañamero, Marta / Martinelli, Paola / Madriles, Francesc / Michl, Patrick / Gress, Thomas / de Pascual, Ricardo / Gandia, Luis / Guerra, Carmen / Barbacid, Mariano / Wagner, Martin / Vieira, Catarina R / Aicher, Alexandra / Real, Francisco X / Sainz, Bruno / Heeschen, Christopher. ·Stem Cells and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. · Comparative Pathology Core Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. · Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. · Department of Gastroenterology, Endocrinology, Metabolism and Infectiology, University of Marburg, Marburg, Germany. · Instituto Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain. · Experimental Oncology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. · Department of Internal Medicine I, Ulm University, Ulm, Germany. · Stem Cells and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. Electronic address: bruno.sainz@uam.es. · Stem Cells and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Centre for Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, UK. Electronic address: c.heeschen@qmul.ac.uk. ·Gastroenterology · Pubmed #25127677.

ABSTRACT: BACKGROUND & AIMS: Although smoking is a leading risk factor for pancreatic ductal adenocarcinoma (PDAC), little is known about the mechanisms by which smoking promotes initiation or progression of PDAC. METHODS: We studied the effects of nicotine administration on pancreatic cancer development in Kras(+/LSLG12Vgeo);Elas-tTA/tetO-Cre (Ela-KRAS) mice, Kras(+/LSLG12D);Trp53+/LSLR172H;Pdx-1-Cre (KPC) mice (which express constitutively active forms of KRAS), and C57/B6 mice. Mice were given nicotine for up to 86 weeks to produce blood levels comparable with those of intermediate smokers. Pancreatic tissues were collected and analyzed by immunohistochemistry and reverse transcriptase polymerase chain reaction; cells were isolated and assayed for colony and sphere formation and gene expression. The effects of nicotine were also evaluated in primary pancreatic acinar cells isolated from wild-type, nAChR7a(-/-), Trp53(-/-), and Gata6(-/-);Trp53(-/-) mice. We also analyzed primary PDAC cells that overexpressed GATA6 from lentiviral expression vectors. RESULTS: Administration of nicotine accelerated transformation of pancreatic cells and tumor formation in Ela-KRAS and KPC mice. Nicotine induced dedifferentiation of acinar cells by activating AKT-ERK-MYC signaling; this led to inhibition of Gata6 promoter activity, loss of GATA6 protein, and subsequent loss of acinar differentiation and hyperactivation of oncogenic KRAS. Nicotine also promoted aggressiveness of established tumors as well as the epithelial-mesenchymal transition, increasing numbers of circulating cancer cells and their dissemination to the liver, compared with mice not exposed to nicotine. Nicotine induced pancreatic cells to acquire gene expression patterns and functional characteristics of cancer stem cells. These effects were markedly attenuated in K-Ras(+/LSL-G12D);Trp53(+/LSLR172H);Pdx-1-Cre mice given metformin. Metformin prevented nicotine-induced pancreatic carcinogenesis and tumor growth by up-regulating GATA6 and promoting differentiation toward an acinar cell program. CONCLUSIONS: In mice, nicotine promotes pancreatic carcinogenesis and tumor development via down-regulation of Gata6 to induce acinar cell dedifferentiation.

25 Article Synthetic lethality screen identifies RPS6KA2 as modifier of epidermal growth factor receptor activity in pancreatic cancer. 2013

Milosevic, Nada / Kühnemuth, Benjamin / Mühlberg, Leonie / Ripka, Stefanie / Griesmann, Heidi / Lölkes, Carolin / Buchholz, Malte / Aust, Daniela / Pilarsky, Christian / Krug, Sebastian / Gress, Thomas / Michl, Patrick. ·Department of Gastroenterology and Endocrinology, University Hospital, Philipps-University, Marburg, Germany. · Department of Pathology, University Hospital "Carl Gustav Carus", Technical University of Dresden, Dresden, Germany. · Department of Surgery, University Hospital "Carl Gustav Carus", Technical University of Dresden, Dresden, Germany. ·Neoplasia · Pubmed #24403857.

ABSTRACT: Pancreatic cancer is characterized by a high degree of resistance to chemotherapy. Epidermal growth factor receptor (EGFR) inhibition using the small-molecule inhibitor erlotinib was shown to provide a small survival benefit in a subgroup of patients. To identify kinases whose inhibition acts synergistically with erlotinib, we employed a kinome-wide small-interfering RNA (siRNA)-based loss-of-function screen in the presence of erlotinib. Of 779 tested kinases, we identified several targets whose inhibition acted synergistically lethal with EGFR inhibition by erlotinib, among them the S6 kinase ribosomal protein S6 kinase 2 (RPS6KA2)/ribosomal S6 kinase 3. Activated RPS6KA2 was expressed in approximately 40% of 123 human pancreatic cancer tissues. RPS6KA2 was shown to act downstream of EGFR/RAS/mitogen-activated protein kinase kinase (MEK)/extracellular-signal regulated kinase (ERK) signaling and was activated by EGF independently of the presence of KRAS mutations. Knockdown of RPS6KA2 by siRNA led to increased apoptosis only in the presence of erlotinib, whereas RPS6KA2 activation or overexpression rescued from erlotinib- and gemcitabine-induced apoptosis. This effect was at least in part mediated by downstream activation of ribosomal protein S6. Genetic as well as pharmacological inhibition of RPS6KA2 by the inhibitor BI-D1870 acted synergistically with erlotinib. By applying this synergistic lethality screen using a kinome-wide RNA interference-library approach, we identified RPS6KA2 as potential drug target whose inhibition synergistically enhanced the effect of erlotinib on tumor cell survival. This kinase therefore represents a promising drug candidate suitable for the development of novel inhibitors for pancreatic cancer therapy.

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