Institute of Experimental Cancer Research

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Institute of Experimental Cancer Research

Germany

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In totale sono stati arruolati in un rapporto 1:1 (59 pazienti trattati con CT-P10 e 62 pazienti trattati con rituximab di riferimento) 121 pazienti affetti da linfoma follicolare acuto per dimostrare la similarità in termini di farmacocinetica tra CT-P10 e rituximab di riferimento, entrambi in combinazione con chemioterapia standard a base di ciclofosfamide, vincristina e prednisone (CVP). I risultati dello studio clinico randomizzato, in doppio cieco e controllato hanno rilevato profili similari in termini di farmacocinetica e farmacodinamica (PD), immunogenicità e sicurezza tra CT-P10 e rituximab di riferimento fino a 12 settimane. 1 Il Dr. Bertrand Coiffier, ricercatore responsabile globale dello studio sulla LFA, responsabile del Dipartimento di ematologia presso gli Hospices Civils de Lyon e docente dell'Università Claude Bernard, di Lione, in Francia, ha dichiarato: " I risultati presentati oggi mostrano profili similari in termini di PK e profili comparabili in termini di cinetica delle cellule B, immunogenicità e sicurezza tra biosimilare rituximab CT-P10 e rituximab di riferimento nei pazienti affetti da LFA, a conferma dei risultati comparabili degli studi clinici sui pazienti affetti da AR. Il programma complessivo offre prove sostanziali e convincenti della similarità tra CT-P10 e rituximab di riferimento. " Si prevede che la disponibilità di biosimilare rituximab CT-P10 per il trattamento dei pazienti affetti da malattie linfoproliferative ridurrà i costi di trattamento, permettendo potenzialmente a più pazienti di iniziare ad assumere rituximab non solo per la fase di induzione, ma anche per quelle di manutenzione e consolidamento". Man Hoon Kim, presidente e CEO di Celltrion Healthcare, ha dichiarato: " Sulla base di tutte le prove raccolte dal nostro programma clinico globale, riteniamo che CT-P10 rappresenti un'alternativa al prodotto di riferimento dal buon rapporto costo-efficacia in grado di migliorare l'accesso dei pazienti e, in ultima istanza, di ridurre il costo dell'utilizzo di rituximab in diverse indicazioni in campo autoimmunitario e oncologico in numerosi paesi del mondo". Christian Buske, professore e direttore medico del Comprehensive Cancer Center di Ulm, in Germania, direttore dell'Institute of Experimental Cancer Research, medico e professore di Medicina presso il Dipartimento medico di medicina Interna III, Divisione di Ematologia/Oncologia, ha dichiarato: " Sulla base dei dati dello studio sulla LFA, in qualità di ematologo e oncologo, accolgo con favore lo sviluppo di nuove opzioni terapeutiche che potrebbero facilitare e ampliare l'accesso a terapie efficaci e convenienti da parte dei pazienti affetti da linfoma. La disponibilità di un biosimilare rituximab può migliorare enormemente l'accesso dei pazienti affetti da disturbi linfoidi maligni a un trattamento a base di un anticorpo diretto contro il CD20 estremamente efficiente". Michinori Ogura, professore e direttore del Dipartimento di ematologia presso il Tokai Central Hospital, in Giappone, ha affermato: " È evidente la similarità tra CT-P10 e rituximab di riferimento in termini di PK, di deplezione delle cellule B, di sicurezza e immunogenicità in 4 cicli terapici. Avendo partecipato in numerosi studi clinici su rituximab, posso affermare che i dati riferiti alla farmacologia clinica e alla sicurezza sono in linea con altri studi a cui ho collaborato in passato. Si prevede quindi che CT-P10 darà risultati simili a rituximab di riferimento nell'ambiente clinico per tutte le indicazioni e le condizioni d'uso. Ovviamente è necessario disporre di dati a lungo termine sull'efficacia e la tossicità". CT-P10 è un rituximab biosimilare candidato. I risultati più importanti del primo studio clinico su CT-P10, uno studio clinico controllato randomizzato di fase 1 rispetto a rituximab di riferimento nei pazienti con AR attiva, sono stati pubblicati di recente e dimostrano che la farmacocinetica (PK) dei due farmaci dopo un unico ciclo di trattamento risultava statisticamente equivalente, e che la loro efficacia, farmacodinamica (PD), immunogenicità e sicurezza erano simili fino alla settimana 245 I dati clinici dello studio di estensione di fase 1 di 72 settimane e un ulteriore studio sul passaggio al prodotto biosimilare sono stati presentati alla conferenza 2015 dell'American College of Rheumatology6 e al congresso annuale 2016 della European Union League Against Rheumatism.4 Sono in corso 3 studi clinici controllati e randomizzati sui pazienti affetti da AR (NCT02149121), LFA (NCT02162771) e da linfoma follicolare a basso carico tumorale (LTBFL) (NCT02260804). È stata dimostrata l'equivalenza in termini di farmacocinetica e di efficacia tra CT-P10 e rituximab di rifermento, con successiva presentazione dei risultati al congresso ACR 2016.3 I linfomi follicolari rappresentano per diffusione il secondo sottotipo dei tumori maligni dei linfonodi nell'Europa occidentale7 e costituiscono un sottotipo del linfoma non-Hodgkin.8 Si tratta di un linfoma a crescita lenta che si sviluppa dai linfociti B (cellule B).10 Si caratterizza per il gonfiore indolore dei linfonodi e per febbre senza ragione apparente, sudori notturni, affaticamento, infezioni e sanguinamento. 10 Al momento della diagnosi molti casi si presentano in stadio già avanzato, ma dal lancio di rituximab la sopravvivenza globale è aumentata fino a superare i 20 anni. 10 Prende il nome di linfoma 'follicolare' a causa della crescita abnorme dei linfociti spesso raggruppati in grumi detti 'follicoli' situati nei linfonodi. 10 Il linfoma follicolare è maggiormente comune nelle persone di oltre 65 anni, ma può colpire pazienti di ogni età. 10 Celltrion Healthcare effettua attività di marketing, vendita e distribuzione dei biofarmaci sviluppati da Celltrion, Inc. a livello mondiale tramite un'estesa rete internazionale che comprende oltre 120 diversi paesi. I prodotti di Celltrion Healthcare sono realizzati a partire da colture cellulari di mammiferi in avanzate strutture progettate e costruite in conformità agli standard cGMP della Food and Drug Administration (FDA) statunitense e agli standard GMP della UE. Per ulteriori informazioni visitare il sito: http://www.celltrionhealthcare.com/ 1 B. Coiffier, et al. Pharmacokinetic and Safety of CT-P10, a Biosimilar Candidate to the Rituximab Reference Product, in Patients with Newly Diagnosed Advanced Stage Follicular Lymphoma (AFL). 58th Annual Meeting and Exposition of the American Society of Hematology 2016; 1807. 2 Suh, CH. et al. Pharmacokinetics and Safety of Three Formulations of Rituximab (CT-P10, US-sourced Innovator Rituximab and EU-sourced Innovator Rituximab) in Patients with Rheumatoid Arthritis: Results from Phase 3 Randomized Controlled Trial over 24 Weeks. American College of Rheumatology/Association of Rheumatology Health Professionals Annual Meeting 2016; 1634. 3 Yoo, DH, et al. Efficacy and Safety of CT-P10, Rituximab Biosimilar Candidate, and Innovator Rituximab in Patients with Rheumatoid Arthritis: Results from Phase 3 Randomized Controlled Trial over 24 Weeks. American College of Rheumatology/Association of Rheumatology Health Professionals Annual Meeting 2016; 1635. 4 Park, W. et al. THU0162 Comparable Time to Retreatment between CT-P10 and Innovator Rituximab up to 2 Years in Patients with Active Rheumatoid Arthritis. Annals of the Rheumatic Diseases. 2016 Jun 1;75(Suppl 2):241-2. 5 Yoo, DH, et al. A multicentre randomised controlled trial to compare the pharmacokinetics, efficacy and safety of CT-P10 and innovator rituximab in patients with rheumatoid arthritis. Annals of the Rheumatic Diseases. 2016;annrheumdis-2016-209540. 6 Yoo, DH, et al. Efficacy and Safety of Rituximab Biosimilar Candidate (CT-P10) and Innovator Rituximab in Patients with Rheumatoid Arthritis: Results from Phase I Randomized Controlled Trial over 72 Weeks. Arthritis & Rheumatology. 2015;Vol 67. 7 Dreyling, M, et al. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2011;22(suppl 6):vi59-vi63. 8 Kohrt HEK & Ugarte A. Follicular Lymphoma: a Guide for Patients. European Society for Medical Oncology. 2014. Available at: https://www.esmo.org/content/download/52236/963497/file/EN-Follicular-Lymphoma-Guide-for-Patients.pdf [ultimo accesso novembre 2016].


SAN DIEGO--(BUSINESS WIRE)--New data presented at the 2016 American Society of Hematology (ASH) Annual Meeting demonstrate that CT-P10 (biosimilar rituximab candidate) and reference rituximab are equivalent in terms of pharmacokinetics (PK) in patients with advanced follicular lymphoma (AFL), a form of non-Hodgkin lymphoma. 1 A total of 121 AFL patients were enrolled in a 1:1 ratio (59 patients on CT-P10 and 62 patients on reference rituximab) to demonstrate PK similarity of CT-P10 to reference rituximab, each given in combination with standard chemotherapy of cyclophosphamide, vincristine, and prednisone (CVP). The results from the randomized, double-blind, controlled study found equivalent PK and similar pharmacodynamics (PD), immunogenicity and safety profiles of CT-P10 to those of reference rituximab for up to 12 weeks. 1 This evidence of similarity builds on clinical experience of CT-P10 along with the data in patients with rheumatoid arthritis (RA), which shows compelling similarity in PK, PD, efficacy, safety and immunogenicity and was presented at the 2016 American College of Rheumatology (ACR) Annual Meeting and the Annual European Congress of Rheumatology (EULAR).2,3,4 Dr. Bertrand Coiffier, the global principle investigator of the AFL study, Head of the Department of Hematology at Hospices Civils de Lyon and Professor at the University Claude Bernard, Lyon, France, said: “ The results presented today show similar PK and comparable B cell kinetics, immunogenicity and safety profiles between CT-P10 biosimilar rituximab and reference rituximab in patients with AFL, confirming comparable results in clinical studies in patients with RA. The overall program provides substantial and convincing evidence for similarity between CT-P10 and reference rituximab. “ The availability of CT-P10 biosimilar rituximab for treatment of patients with lymphoproliferative disorders is expected to reduce costs of treatment, potentially enabling more patients to initiate rituximab treatment not only through induction but also maintenance and consolidation phases of treatment.” Man Hoon Kim, President and CEO of Celltrion Healthcare, said: “ Based on the totality of evidence collected from our global clinical programme, we believe that CT-P10 is a cost-effective alternative to the reference product. It could improve patient access and ultimately reduce the cost of rituximab use across autoimmune and oncology indications in many countries throughout the world.” Christian Buske, Professor, Medical Director – Comprehensive Cancer Center Ulm, Germany, Institute of Experimental Cancer Research and Attending Physician and Professor of Medicine at the Medical Department for Internal Medicine III, Hematology/Oncology, said: “ Based on the data from AFL, I, as a haematologist/oncologist, welcome the development of new therapeutic options that could facilitate and broaden access of lymphoma patients to efficacious and affordable therapies. The availability of a biosimilar rituximab can tremendously improve access of patients with malignant lymphoid disorders to highly efficient anti-CD20 antibody treatment.” Michinori Ogura, Professor, Director of the Department of Hematology at Tokai Central Hospital, Japan, said:" The similarity in PK, B-cell depletion, safety and immunogenicity through 4 cycles of therapy were shown between CT-P10 and reference rituximab. Having being involved in numerous clinical studies with rituximab, the results in terms of clinical pharmacology and safety data are consistent with other studies I have been involved in the past. Therefore, CT-P10 is anticipated to perform similarly to the reference rituximab in the clinical setting across indications and conditions of use. Of course, it remains to have long-term data of efficacy and toxicity.” Rituximab is a CD20-directed cytolytic antibody indicated for the treatment of patients with non-Hodgkin’s lymphoma (NHL), chronic lymphocytic leukemia (CLL), rheumatoid arthritis (RA), granulomatosis with polyangiitis, and microscopic polyangiitis. CT-P10 is a rituximab biosimilar candidate. The primary results of the first clinical study of CT-P10 – a phase 1 RCT versus reference rituximab in patients with active RA – were recently published and demonstrated the pharmacokinetics (PK) of the two drugs after a single course of treatment were statistically equivalent, and that their efficacy, pharmacodynamics (PD), immunogenicity, and safety were similar up to week 24.5 The clinical data of phase 1 72-week extension study and an additional 1-year switching study were presented at the American College of Rheumatology’s 2015 meeting6 and the annual European Union League Against Rheumatism congress in 2016.4 Three phase 3 RCT studies in patients with RA (NCT02149121), AFL (NCT02162771) and low-tumor-burden follicular lymphoma (LTBFL) (NCT02260804) are ongoing. Equivalent pharmacokinetics and efficacy were demonstrated between CT-P10 and reference rituximab and presented in ACR 2016.3 Follicular lymphomas are the second most frequent subtype of nodal lymphoid malignancies in Western Europe7 and is a subtype of NHL.8 It is a slow-growing lymphoma that develops from B lymphocytes (B cells).10 It is characterized by painless swelling of the lymph nodes, fever for no apparent reason, drenching night sweats, fatigue, infections and bleeding. 10 Most cases are advanced at the time of diagnosis but since the advent of rituximab, overall survival has increased to in excess of 20 years. 10 It is called ‘follicular’ lymphoma because the abnormal lymphocytes often collect in lymph nodes in clumps that are known as ‘follicles’. 10 Follicular lymphoma is more common in people aged over 65, but it can occur in people of any age. 10 Celltrion Healthcare conducts the worldwide marketing, sales and distribution of biological medicines developed by Celltrion, Inc. through an extensive global network that spans more than 120 different countries. Celltrion Healthcare’s products are manufactured at state-of-the-art mammalian cell culture facilities, designed and built to comply with the US Food and Drug Administration (FDA) cGMP guidelines and the EU GMP guidelines. For more information please visit: http://www.celltrionhealthcare.com/ 1 B. Coiffier, et al. Pharmacokinetic and Safety of CT-P10, a Biosimilar Candidate to the Rituximab Reference Product, in Patients with Newly Diagnosed Advanced Stage Follicular Lymphoma (AFL). 58th Annual Meeting and Exposition of the American Society of Hematology 2016; 1807. 2 Suh, CH. et al. Pharmacokinetics and Safety of Three Formulations of Rituximab (CT-P10, US-sourced Innovator Rituximab and EU-sourced Innovator Rituximab) in Patients with Rheumatoid Arthritis: Results from Phase 3 Randomized Controlled Trial over 24 Weeks. American College of Rheumatology/Association of Rheumatology Health Professionals Annual Meeting 2016; 1634. 3 Yoo, DH, et al. Efficacy and Safety of CT-P10, Rituximab Biosimilar Candidate, and Innovator Rituximab in Patients with Rheumatoid Arthritis: Results from Phase 3 Randomized Controlled Trial over 24 Weeks. American College of Rheumatology/Association of Rheumatology Health Professionals Annual Meeting 2016; 1635. 4 Park, W. et al. THU0162 Comparable Time to Retreatment between CT-P10 and Innovator Rituximab up to 2 Years in Patients with Active Rheumatoid Arthritis. Annals of the Rheumatic Diseases. 2016 Jun 1;75(Suppl 2):241-2. 5 Yoo, DH, et al. A multicentre randomised controlled trial to compare the pharmacokinetics, efficacy and safety of CT-P10 and innovator rituximab in patients with rheumatoid arthritis. Annals of the Rheumatic Diseases. 2016;annrheumdis-2016-209540. 6 Yoo, DH, et al. Efficacy and Safety of Rituximab Biosimilar Candidate (CT-P10) and Innovator Rituximab in Patients with Rheumatoid Arthritis: Results from Phase I Randomized Controlled Trial over 72 Weeks. Arthritis & Rheumatology. 2015;Vol 67. 7 Dreyling, M, et al. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2011;22(suppl 6):vi59-vi63. 8 Kohrt HEK & Ugarte A. Follicular Lymphoma: a Guide for Patients. European Society for Medical Oncology. 2014. Available at: https://www.esmo.org/content/download/52236/963497/file/EN-Follicular-Lymphoma-Guide-for-Patients.pdf [accessed November 2016].


Kurbitz C.,Institute of Experimental Cancer Research | Heise D.,Institute of Experimental Cancer Research | Redmer T.,Max Delbrück Center for Molecular Medicine | Goumas F.,University of Kiel | And 5 more authors.
Cancer Science | Year: 2011

Green tea catechins are considered as possible cancer preventive agents for several cancer types but little is known regarding their effects on pancreatic cancer cells. The best studied catechin and the major polyphenol present in green tea is epigallocatechin gallate (EGCG). In the present study, we investigated the in vitro anti-tumoral properties of EGCG on human pancreatic ductal adenocarcinoma (PDAC) cells PancTu-I, Panc1, Panc89 and BxPC3 in comparison with the effects of two minor components of green tea catechins, catechin gallate (CG) and epicatechin gallate (ECG). We found that all three catechins inhibited proliferation of PDAC cells in a dose- and time-dependent manner. Interestingly, CG and ECG exerted much stronger anti-proliferative effects than EGCG. Western blot analyses performed with PancTu-I cells revealed catechin-mediated modulation of cell cycle regulatory proteins (cyclins, cyclin-dependent kinases [CDK], CDK inhibitors). Again, these effects were clearly more pronounced in CG or ECG than in EGCG-treated cells. Importantly, catechins, in particular ECG, inhibited TNFα-induced activation of NF-κB and consequently secretion of pro-inflammatory and invasion promoting proteins like IL-8 and uPA. Overall, our data show that green tea catechins ECG and CG exhibit potent and much stronger anti-proliferative and anti-inflammatory activities on PDAC cells than the most studied catechin EGCG. © 2011 Japanese Cancer Association.


Chen L.,Dana-Farber Cancer Institute | Chen L.,Harvard University | Deshpande A.J.,Dana-Farber Cancer Institute | Banka D.,Dana-Farber Cancer Institute | And 9 more authors.
Leukemia | Year: 2013

The t(10;11)(p12;q23) translocation and the t(10;11)(p12;q14) translocation, which encode the MLL (mixed lineage leukemia)-AF10 and CALM (clathrin assembly lymphoid myeloid leukemia)-AF10 fusion oncoproteins, respectively, are two recurrent chromosomal rearrangements observed in patients with acute myeloid leukemia and acute lymphoblastic leukemia. Here, we demonstrate that MLL-AF10 and CALM-AF10-mediated transformation is dependent on the H3K79 methyltransferase Dot1l using genetic and pharmacological approaches in mouse models. Targeted disruption of Dot1l using a conditional knockout mouse model abolished in vitro transformation of murine bone marrow cells and in vivo initiation and maintenance of MLL-AF10 or CALM-AF10 leukemia. The treatment of MLL-AF10 and CALM-AF10 transformed cells with EPZ004777, a specific small-molecule inhibitor of Dot1l, suppressed expression of leukemogenic genes such as Hoxa cluster genes and Meis1, and selectively impaired proliferation of MLL-AF10 and CALM-AF10 transformed cells. Pretreatment with EPZ004777 profoundly decreased the in vivo spleen-colony-forming ability of MLL-AF10 or CALM-AF10 transformed bone marrow cells. These results show that patients with leukemia-bearing chromosomal translocations that involve the AF10 gene may benefit from small-molecule therapeutics that inhibit H3K79 methylation. © 2013 Macmillan Publishers Limited All rights reserved.


Schmid F.,University of Ulm | Schmid M.,University of Bonn | Mussel C.,University of Ulm | Strang J.E.,University of Ulm | And 5 more authors.
Bioinformatics | Year: 2016

Over the past years growing knowledge about biological processes and pathways revealed complex interaction networks involving many genes. In order to understand these networks, analysis of differential expression has continuously moved from single genes towards the study of gene sets. Various approaches for the assessment of gene sets have been developed in the context of gene set analysis (GSA). These approaches are bridging the gap between raw measurements and semantically meaningful terms. We present a novel approach for assessing uncertainty in the definition of gene sets. This is an essential step when new gene sets are constructed from domain knowledge or given gene sets are suspected to be affected by uncertainty. Quantification of uncertainty is implemented in the R-package GiANT. We also included widely used GSA methods, embedded in a generic framework that can readily be extended by custom methods. The package provides an easy to use front end and allows for fast parallelization. Availability and implementation: The package GiANT is available on CRAN. Contacts: or hans.kestler@uni-Ulm.de. © 2016 The Author 2016.


Wu Y.,Institute of Organic Chemistry III | Wu Y.,Max Planck Institute for Polymer Research | Ihme S.,Institute of Experimental Cancer Research | Feuring-Buske M.,Institute of Experimental Cancer Research | And 8 more authors.
Advanced Healthcare Materials | Year: 2013

The native transportation protein serum albumin represents an attractive nano-sized transporter for drug delivery applications due to its beneficial safety profile. Existing albumin-based drug delivery systems are often limited by their low drug loading capacity as well as noticeable drug leakage into the blood circulation. Therefore, a unique albumin-derived core-shell doxorubicin (DOX) delivery system based on the protein denaturing-backfolding strategy was developed. 28 DOX molecules were covalently conjugated to the albumin polypeptide backbone via an acid sensitive hydrazone linker. Polycationic and pegylated human serum albumin formed two non-toxic and enzymatically degradable protection shells around the encapsulated DOX molecules. This core-shell delivery system possesses notable advantages, including a high drug loading capacity critical for low administration doses, a two-step drug release mechanism based on pH and the presence of proteases, an attractive biocompatibility and narrow size distribution inherited from the albumin backbone, as well as fast cellular uptake and masking of epitopes due to a high degree of pegylation. The IC50 of these nanoscopic onion-type micelles was found in the low nanomolar range for Hela cells as well as leukemia cell lines. In vivo data indicate its attractive potential as anti-leukemia treatment suggesting its promising profile as nanomedicine drug delivery system. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Helm O.,Institute for Experimental Medicine | Mennrich R.,Institute for Experimental Medicine | Petrick D.,Institute of Immunology | Goebel L.,Institute for Experimental Medicine | And 10 more authors.
PLoS ONE | Year: 2014

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive stroma being also present in chronic pancreatitis (CP). Using immunohistochemistry, the stroma of CP and PDAC was comprehensively analyzed and correlated with epithelial/carcinoma-related alterations and clinicopathological patient characteristics. While there were no significant differences between CP and PDAC regarding the distribution of CD3+ T cells and α-SMA+ fibroblasts, proportions of CD4+ and CD8+ T cells were significantly lower and numbers of CD25+(CD4+) and FoxP3+(CD4 +) regulatory T cells were greater in PDAC compared with CP. Macrophages were more prevalent in CP, but localized more closely to carcinoma cells in PDAC, as were γδ-T cells. Duct-related FoxP3 and L1CAM expression increased from CP to PDAC, while vimentin expression was similarly abundant in both diseases. Moreover, stromal and epithelial compartments of well-differentiated tumors and CPs shared considerable similarities, while moderately and poorly differentiated tumors significantly differed from CP tissues. Analysis of 27 parameters within each pancreatic disease revealed a significant correlation of i) CD4+ and FoxP3+CD4+ T cells with FoxP3 expression in PDAC cells, ii) α-SMA+ fibroblasts with L1CAM expression and proliferation in PDAC cells, iii) CD3 and CD8 expression with γδ-TCR expression in both pancreatic diseases and iv) CD68+ and CD163+ macrophages with vimentin expression in PDAC cells. High expression of FoxP3, vimentin and L1CAM in PDAC cells as well as a tumor-related localization of macrophages each tended to correlate with higher tumor grade. Multivariate survival analysis revealed a younger age at time of surgery as a positive prognostic marker for PDAC patients with the most frequently operated disease stage T3N1M0. Overall this study identified several interrelationships between stroma and epithelial/carcinoma cells in PDACs but also in CP, which in light of previous experimental data strongly support the view that the inflammatory stroma contributes to malignancy-associated alterations already in precursor cells during CP. © 2014 Helm et al.


Lemke J.,Institute of Experimental Cancer Research | Noack A.,Institute of Experimental Cancer Research | Adam D.,Institute of Immunology | Tchikov V.,Institute of Immunology | And 6 more authors.
Journal of Molecular Medicine | Year: 2010

Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) and agonistic anti-DR4/TRAIL-R1 and anti-DR5/TRAIL-R2 antibodies are currently under clinical investigation for treatment of different malignancies. TRAIL activates DR4 and DR5 and thereby triggers apoptotic and non-apoptotic signaling pathways, but possible different roles of DR4 or DR5 in these responses has poorly been addressed so far. In the present work, we analyzed cell viability, DISC formation as well as IL-8 and NF-κB activation side by side in responses to TRAIL and agonistic antibodies against DR4 (mapatumumab) and against DR5 (lexatumumab) in pancreatic ductal adenocarcinoma cells. We found that all three reagents are able to activate cell death and pro-inflammatory signaling. Death-inducing signaling complex (DISC) analysis revealed that mapatumumab and lexatumumab induce formation of homocomplexes of either DR4 or DR5, whereas TRAIL additionally stimulated the formation of heterocomplexes of both receptors. Notably, blocking of receptors using DR4- and DR5-specific Fab fragments indicated that TRAIL exerted its function predominantly via DR4. Interestingly, inhibition of PKC by Goe6983 enabled DR5 to trigger apoptotic signaling in response to TRAIL and also strongly enhanced lexatumumab-mediated cell death. Our results suggest the existence of mechanisms that silence DR5 for TRAIL- but not for agonistic-antibody treatment. © 2010 Springer-Verlag.


Ehrenschwender M.,University of Würzburg | Siegmund D.,University of Würzburg | Wicovsky A.,University of Würzburg | Kracht M.,Justus Liebig University | And 6 more authors.
Cell Death and Differentiation | Year: 2010

Constitutively active PI3K catalytic subunit α (PIK3CA) interfered with apoptosis induction downstream of death receptor-signaling complex formation allowing robust caspase-8 activation without triggering the execution steps of apoptosis. In mutant PIK3CA-expressing cells, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and CD95L stimulated nuclear factor kappaB (NFB) activation, invasion, and transition to an amoeboid-like morphology. NFB activation and adoption of amoeboid shape were inhibited by caspase-8 knockdown or FLIP-S expression, but only the cell morphology alterations required caspase-8 activity. Furthermore, we identified caspase-8-mediated, caspase-3-independent cleavage of the protein kinase rho-associated, coiled-coil containing protein kinase 1 as a novel mechanism for acquiring amoeboid shape and enhanced invasiveness in response to TRAIL and CD95L. Taken together, we provide evidence that mutated PIK3CA converts the tumor surveillance activity of cancer cell-expressed death receptors and caspase-8 toward tumor promotion. © 2010 Macmillan Publishers Limited. All rights reserved.


PubMed | University of Bonn, Institute of Experimental Cancer Research and University of Ulm
Type: Journal Article | Journal: Bioinformatics (Oxford, England) | Year: 2016

Over the past years growing knowledge about biological processes and pathways revealed complex interaction networks involving many genes. In order to understand these networks, analysis of differential expression has continuously moved from single genes towards the study of gene sets. Various approaches for the assessment of gene sets have been developed in the context of gene set analysis (GSA). These approaches are bridging the gap between raw measurements and semantically meaningful terms.We present a novel approach for assessing uncertainty in the definition of gene sets. This is an essential step when new gene sets are constructed from domain knowledge or given gene sets are suspected to be affected by uncertainty. Quantification of uncertainty is implemented in the R-package GiANT. We also included widely used GSA methods, embedded in a generic framework that can readily be extended by custom methods. The package provides an easy to use front end and allows for fast parallelization.The package GiANT is available on CRAN.hans.kestler@leibniz-fli.de or hans.kestler@uni-ulm.de.

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