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Dive into the research topics where Klaus Giese is active.

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Featured researches published by Klaus Giese.


Cancer Research | 2008

Atu027, a Liposomal Small Interfering RNA Formulation Targeting Protein Kinase N3, Inhibits Cancer Progression

Manuela Aleku; Petra Schulz; Oliver Keil; Ansgar Santel; Ute Schaeper; Britta Dieckhoff; Oliver Janke; Jens Endruschat; Birgit Durieux; Nadine Röder; Kathrin Löffler; Christian Lange; Melanie Fechtner; Kristin Möpert; Gerald Fisch; Sibylle Dames; Wolfgang Arnold; Karin Jochims; Klaus Giese; Bertram Wiedenmann; Arne Scholz; Jörg Kaufmann

We have previously described a small interfering RNA (siRNA) delivery system (AtuPLEX) for RNA interference (RNAi) in the vasculature of mice. Here we report preclinical data for Atu027, a siRNA-lipoplex directed against protein kinase N3 (PKN3), currently under development for the treatment of advanced solid cancer. In vitro studies revealed that Atu027-mediated inhibition of PKN3 function in primary endothelial cells impaired tube formation on extracellular matrix and cell migration, but is not essential for proliferation. Systemic administration of Atu027 by repeated bolus injections or infusions in mice, rats, and nonhuman primates results in specific, RNAi-mediated silencing of PKN3 expression. We show the efficacy of Atu027 in orthotopic mouse models for prostate and pancreatic cancers with significant inhibition of tumor growth and lymph node metastasis formation. The tumor vasculature of Atu027-treated animals showed a specific reduction in lymph vessel density but no significant changes in microvascular density.


Journal of Biological Chemistry | 2000

The I kappa B kinase (IKK) complex is tripartite and contains IKK gamma but not IKAP as a regular component.

Daniel Krappmann; Eunice N. Hatada; Sebastian Tegethoff; Jun Li; Anke Klippel; Klaus Giese; Patrick Baeuerle; Claus Scheidereit

A critical step in the activation of NF-κB is the phosphorylation of IκBs by the IκB kinase (IKK) complex. IKKα and IKKβ are the two catalytic subunits of the IKK complex and two additional molecules, IKKγ/NEMO and IKAP, have been described as further integral members. We have analyzed the function of both proteins for IKK complex composition and NF-κB signaling. IKAP and IKKγ belong to distinct cellular complexes. Quantitative association of IKKγ was observed with IKKα and IKKβ. In contrast IKAP was complexed with several distinct polypeptides. Overexpression of either IKKγ or IKAP blocked tumor necrosis factor α induction of an NF-κB-dependent reporter construct, but IKAP in addition affected several NF-κB-independent promoters. Whereas specific down-regulation of IKKγ protein levels by antisense oligonucleotides significantly reduced cytokine-mediated activation of the IKK complex and subsequent NF-κB activation, a similar reduction of IKAP protein levels had no effect on NF-κB signaling. Using solely IKKα, IKKβ, and IKKγ, we could reconstitute a complex whose apparent molecular weight is comparable to that of the endogenous IKK complex. We conclude that while IKKγ is a stoichiometric component of the IKK complex, obligatory for NF-κB signaling, IKAP is not associated with IKKs and plays no specific role in cytokine-induced NF-κB activation.


Oncogene | 2005

REDD1 integrates hypoxia-mediated survival signaling downstream of phosphatidylinositol 3-kinase

Rolf Schwarzer; Daniel Tondera; Wolfgang Arnold; Klaus Giese; Anke Klippel; Jörg Kaufmann

Cancer cells frequently evade apoptosis during tumorigenesis by acquiring mutations in apoptotic regulators. Chronic activation of the PI 3-kinase-Akt pathway through loss of the tumor suppressor PTEN is one mechanism by which these cells can gain increased protection against apoptosis. We report here that REDD1 (RTP801) can act as a transcriptional downstream target of PI 3-kinase signaling in human prostate cancer cells (PC-3). REDD1 expression is markedly reduced in PC-3 cells treated with LY294002 (LY) or Rapamycin and strongly induced under hypoxic conditions in a hypoxia-inducible factor-1 (HIF-1)-dependent manner. Loss of function studies employing antisense molecules or RNA interference indicate that REDD1 is essential for invasive growth of prostate cancer cells in vitro and in vivo. Reduced REDD1 levels can sensitize cells towards apoptosis, whereas elevated levels of REDD1 induced by hypoxia or overexpression desensitize cells to apoptotic stimuli. Taken together our data designate REDD1 as a novel target for therapeutic intervention in prostate cancer.


principles and practice of constraint programming | 2012

Phase I clinical development of Atu027, a siRNA formulation targeting PKN3 in patients with advanced solid tumors

Dirk Strumberg; Beate Schultheis; Ulrich Traugott; Christiane Vank; Ansgar Santel; Oliver Keil; Klaus Giese; Jörg Kaufmann; Joachim Drevs

Chemically synthesized, small interfering RNAs (siRNA) are currently used as a new class of therapeutic molecules, allowing the controlled down-regulation of pathologically relevant gene expression e.g., oncogenes and other similar targets in cancer [1, 2, 3].However, the overall negative charge of siRNA molecules (up to 40 negative charg-es) and the relatively high molecular weight (12,000 – 14,000 Da) prevent the functional uptake of these novel therapeutic molecules in vivo. Besides the inefficient uptake and the degradation in endosomal compartments at the cellular level, non-formulated siRNAs are rapidly cleared by renal excretion from the blood stream when administered i.v. [4].To overcome these limitations, a variety of non-viral nanoparticles (50 – 200 nm) have been recently developed enabling chemically synthesized siRNA to be used therapeuti-cally for inhibition of RNAi-mediated tumor growth. Atu027 is a novel RNAi therapeutic agent based on cationic lipoplexes containing chemically stabilized siRNAs, which target Protein Kinase N3 (PKN3) gene expression in the vascular endothelium (Figure 1) [5]. PKN3, a member of the AGC kinase fam-ily, has been identified as a promising, novel therapeutic target in cancer cells for inhibiting tumor progression and lymph node metasta-sis formation [6]. These studies have revealed that PKN3 mediates malignant cell growth downstream of the chronically activated phosphoinositide 3-kinase (PI3K) pathway [6]. Recently, PKN3 has also been considered as a suitable therapeutic target for modulating tumor-associated angiogenesis. Preclinical data, obtained in various cancer mouse mod-els, revealed target-specific, RNAi-mediated silencing of PKN3 expression and significant inhibition of tumor progression and metasta-sis formation [


The EMBO Journal | 2004

PKN3 is required for malignant prostate cell growth downstream of activated PI 3‐kinase

Frauke Leenders; Kristin Möpert; Anett Schmiedeknecht; Ansgar Santel; Frank Czauderna; Manuela Aleku; Silke Penschuck; Sibylle Dames; Maria Sternberger; Thomas Röhl; Axel Wellmann; Wolfgang Arnold; Klaus Giese; Jörg Kaufmann; Anke Klippel

Chronic activation of the phosphoinositide 3‐kinase (PI3K)/PTEN signal transduction pathway contributes to metastatic cell growth, but up to now effectors mediating this response are poorly defined. By simulating chronic activation of PI3K signaling experimentally, combined with three‐dimensional (3D) culture conditions and gene expression profiling, we aimed to identify novel effectors that contribute to malignant cell growth. Using this approach we identified and validated PKN3, a barely characterized protein kinase C‐related molecule, as a novel effector mediating malignant cell growth downstream of activated PI3K. PKN3 is required for invasive prostate cell growth as assessed by 3D cell culture assays and in an orthotopic mouse tumor model by inducible expression of short hairpin RNA (shRNA). We demonstrate that PKN3 is regulated by PI3K at both the expression level and the catalytic activity level. Therefore, PKN3 might represent a preferred target for therapeutic intervention in cancers that lack tumor suppressor PTEN function or depend on chronic activation of PI3K.


Clinical Cancer Research | 2010

Atu027 Prevents Pulmonary Metastasis in Experimental and Spontaneous Mouse Metastasis Models

Ansgar Santel; Manuela Aleku; Nadine Röder; Kristin Möpert; Birgit Durieux; Oliver Janke; Oliver Keil; Jens Endruschat; Sibylle Dames; Christian Lange; Mona Eisermann; Kathrin Löffler; Melanie Fechtner; Gerald Fisch; Christiane Vank; Ute Schaeper; Klaus Giese; Jörg Kaufmann

Purpose: Atu027, a novel RNA interference therapeutic, has been shown to inhibit lymph node metastasis in orthotopic prostate cancer mouse models. The aim of this study is to elucidate the pharmacologic activity of Atu027 in inhibiting hematogenous metastasis to the target organ lung in four different preclinical mouse models. Experimental Design: Atu027 compared with vehicle or control small interfering RNA lipoplexes was tested in two experimental lung metastasis models (Lewis lung carcinoma, B16V) and spontaneous metastasis mouse models (MDA-MB-435, MDA-MB-231, mammary fat pad). Different dosing schedules (repeated low volume tail vein injections) were applied to obtain insight into effective Atu027 treatment. Primary tumor growth and lung metastasis were measured, and tissues were analyzed by immunohistochemistry and histology. In vitro studies in human umbilical vein endothelial cells were carried out to provide an insight into molecular changes on depletion of PKN3, in support of efficacy results. Results: Intravenous administration of Atu027 prevents pulmonary metastasis. In particular, formation of spontaneous lung metastasis was significantly inhibited in animals with large tumor grafts as well as in mice with resected primary mammary fat pad tumors. In addition, we provide evidence that an increase in VE-cadherin protein levels as a downstream result of PKN3 target gene inhibition may change endothelial function, resulting in reduced colonization and micrometastasis formation. Conclusion: Atu027 can be considered as a potent drug for preventing lung metastasis formation, which might be suitable for preventing hematogenous metastasis in addition to standard cancer therapy. Clin Cancer Res; 16(22); 5469–80. ©2010 AACR.


Antisense & Nucleic Acid Drug Development | 2002

GeneBlocs Are Powerful Tools to Study and Delineate Signal Transduction Processes That Regulate Cell Growth and Transformation

Maria Sternberger; Anett Schmiedeknecht; Anny Kretschmer; Frank Gebhardt; Frauke Leenders; Frank Czauderna; Ira von Carlowitz; Mike Engle; Klaus Giese; Leonid Beigelman; Anke Klippel

The study of signal transduction processes using antisense oligonucleotides is often complicated by low intracellular stability of the antisense reagents or by nonspecific effects that cause toxicity. Here, we introduce a new class of antisense molecules, so-called GeneBlocs, which are characterized by improved stability, high target RNA specificity, and low toxicity. GeneBlocs allow for efficient downregulation of mRNA expression at nanomolar concentrations, and they do not interfere with cell proliferation. We demonstrate these beneficial properties using a positive readout system. GeneBloc-mediated inhibition of tumor suppressor PTEN (phosphatase and tension homologue detected on chromosome 10) expression leads to hyperactivation of the phosphatidylinositol (PI) 3-kinase pathway, thereby mimicking the loss of PTEN function and its early consequences observed in mammalian cancer cells. Specifically, cells treated with PTEN GeneBlocs show functional activation of Akt, a downstream effector of PI 3-kinase signaling, and exhibit enhanced proliferation when seeded on a basement membrane matrix. In addition, GeneBlocs targeting the catalytic subunit of PI 3-kinase, p110, specifically inhibit signal transduction of endogenous or recombinant PI 3-kinase. This demonstrates that GeneBlocs are powerful tools to analyze and to modulate signal transduction processes and, therefore, represent alternative reagents for the validation of gene function.


Molecular Therapy | 2014

Delivery of Therapeutic siRNA to the Lung Endothelium via Novel Lipoplex Formulation DACC

Volker Fehring; Ute Schaeper; Katharina Ahrens; Ansgar Santel; Oliver Keil; M Eisermann; Klaus Giese; Jörg Kaufmann

Posttranscriptional gene silencing by RNA interference can be therapeutically exploited to inhibit pathophysiological gene expression. However, in contrast to the established effectiveness of RNAi in vitro, safe and effective delivery of siRNAs to specific organs and cell types in vivo remains the major hurdle. Here, we report the development and in vivo characterization of a novel siRNA delivery system (DACC lipoplex) suitable for modulating target gene expression specifically in the lung vasculature. Systemic administration of DACC in mice delivered siRNA cargo functionally to the lung pulmonary endothelium. A single dose of DACC lipoplexes administered by bolus injection or by infusion was sufficient to specifically silence genes expressed in pulmonary endothelial cells such as CD31, Tie-2, VE-cadherin, or BMP-R2. When tested in a mouse model for lung cancer, repeated treatment with DACC/siRNA(CD31) reduced formation of lung metastases and increased life span in a mouse model of experimental lung metastasis.


Drug Discovery Today | 2002

Unravelling novel intracellular pathways in cell-based assays.

Klaus Giese; Jörg Kaufmann; Gijsbertus J. Pronk; Anke Klippel

The pharmaceutical industry is currently facing several challenges to identify and develop novel drug targets. Traditional drug discovery focussed on a small number of well-characterized gene products. Recently, this picture has changed with the completion of the draft sequence of the human genome, which has led to the identification of thousands of novel genes with unknown or poorly understood function. To cope with this overwhelming number of potential drug target candidates, new strategies for the elucidation of gene function, as well as their involvement in intracellular pathways, are required.


Nucleic Acids Research | 2003

Structural variations and stabilising modifications of synthetic siRNAs in mammalian cells

Frank Czauderna; Melanie Fechtner; Sibylle Dames; Hüseyin Aygün; Anke Klippel; Gijsbertus J. Pronk; Klaus Giese; Jörg Kaufmann

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Dirk Strumberg

University of Duisburg-Essen

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Hüseyin Aygün

Goethe University Frankfurt

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