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Search Results: 1 - 10 of 1978 matches for " Carsten Bokemeyer "
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TGF-β Superfamily Receptors—Targets for Antiangiogenic Therapy?
Jasmin Otten,Carsten Bokemeyer,Walter Fiedler
Journal of Oncology , 2010, DOI: 10.1155/2010/317068
Abstract: The TGF- pathway controls a broad range of cellular behavior including cell proliferation, differentiation, and apoptosis of various cell types including tumor cells, endothelial cells, immune cells, and fibroblasts. Besides TGF- 's direct effects on tumor growth and its involvement in neoangiogenesis have received recent attention. Germline mutations in TGF- receptors or coreceptors causing Hereditary Hemorrhagic Teleangiectasia and the Loeys-Dietz syndrome underline the involvement of TGF- in vessel formation and maturation. Several therapeutic approaches are evaluated at present targeting the TGF- pathway including utilization of antisense oligonucleotides against TGF- itself or antibodies or small molecule inhibitors of TGF- receptors. Some of these therapeutic agents have already entered the clinical arena including an antibody against the endothelium specific TGF- class I receptor ALK-1 targeting tumor vasculature. In conclusion, therapeutic manipulation of the TGF- pathway opens great opportunities in future cancer therapy. 1. TGF-β Pathway The TGF- superfamily consists of over 30 structurally related multifunctional proteins, including three TGF- isoforms (TGF- 1, 2, and 3), three forms of activin, and over 20 bone morphogenic proteins (BMPs), which control a broad range of cellular behavior such as cell growth, differentiation and apoptosis in various cell types including tumor, immune, and endothelial cells as well as fibroblasts [1–5]. Ligand signaling is mediated through two related single transmembrane type I and type II receptors, which together comprise the only known family of serine/threonine kinases [6–8]. In mammals, there are five different type II (TGFBR2, ActR-IIa, ActR-IIb, BMPR2, AMHRII) and seven type I receptors, also named activin receptor-like kinases (ALK-1-7) [7, 9]. In most cases, the receptor combination is important for the binding of a specific ligand, but the TGF- family members often bind to more than one type II and type I receptor combination [10]. Upon ligand binding, the type I and type II receptors form a heteromeric complex, presumably consisting of two type I and two type II receptors. The type II receptor exhibits a constitutively active kinase which transphosphorylates and activates the type I receptor in a glycine- and serine-rich region known as GS-box [11]. The activated type I receptor propagates the downstream signaling by phosphorylating specific receptor-regulated SMAD proteins (R-SMAD) [12, 13]. R-SMADs interact with SMAD-4, the only known common mediator SMAD (CoSMAD) in mammals, and form heteromeric
Evolving role of cetuximab in the treatment of colorectal cancer
Gunter Schuch, Sebastian Kobold, Carsten Bokemeyer
Cancer Management and Research , 2009, DOI: http://dx.doi.org/10.2147/CMAR.S4750
Abstract: lving role of cetuximab in the treatment of colorectal cancer Review (5653) Total Article Views Authors: Gunter Schuch, Sebastian Kobold, Carsten Bokemeyer Published Date July 2009 Volume 2009:1 Pages 79 - 88 DOI: http://dx.doi.org/10.2147/CMAR.S4750 Gunter Schuch, Sebastian Kobold, Carsten Bokemeyer Department of Oncology, Hematology, and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Abstract: In recent years, the monoclonal epidermal growth factor receptor (EGFR)-targeting antibody cetuximab was introduced into systemic therapy of colorectal cancer and gained an established role in the treatment of this disease. Cetuximab was shown to be active as a single agent in chemorefractory metastatic disease as well as in combination with varying chemotherapies. Recently, randomized trials demonstrated the activity of cetuximab combinations in the first-line setting of metastatic colorectal cancer. Interestingly, the activity of cetuximab was restricted to patients with KRAS wildtype tumors, as was seen with panitumumab, another EGFR antibody. While 60%–70% of tumors harbor KRAS wildtype genes, 30%–40% of tumors express oncogenic KRAS with mutations in codons 12 and 13 causing constitutive activation of signaling cascades downstream of EGFR and resistance to EGFR blockade. Since proof of KRAS wildtype status became a prerequisite for cetuximab treatment, KRAS testing is being established throughout the world. Future trials will address the question which part of the KRAS wildtype cohort will benefit from EGFR inhibition and how to identify those patients. Additionally, new strategies for treatment of KRAS mutated tumors are strongly needed. Recent developments and future strategies will be summarized.
Evolving role of cetuximab in the treatment of colorectal cancer
Gunter Schuch,Sebastian Kobold,Carsten Bokemeyer
Cancer Management and Research , 2009,
Abstract: Gunter Schuch, Sebastian Kobold, Carsten BokemeyerDepartment of Oncology, Hematology, and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyAbstract: In recent years, the monoclonal epidermal growth factor receptor (EGFR)-targeting antibody cetuximab was introduced into systemic therapy of colorectal cancer and gained an established role in the treatment of this disease. Cetuximab was shown to be active as a single agent in chemorefractory metastatic disease as well as in combination with varying chemotherapies. Recently, randomized trials demonstrated the activity of cetuximab combinations in the first-line setting of metastatic colorectal cancer. Interestingly, the activity of cetuximab was restricted to patients with KRAS wildtype tumors, as was seen with panitumumab, another EGFR antibody. While 60%–70% of tumors harbor KRAS wildtype genes, 30%–40% of tumors express oncogenic KRAS with mutations in codons 12 and 13 causing constitutive activation of signaling cascades downstream of EGFR and resistance to EGFR blockade. Since proof of KRAS wildtype status became a prerequisite for cetuximab treatment, KRAS testing is being established throughout the world. Future trials will address the question which part of the KRAS wildtype cohort will benefit from EGFR inhibition and how to identify those patients. Additionally, new strategies for treatment of KRAS mutated tumors are strongly needed. Recent developments and future strategies will be summarized.Keywords: cetuximab, colorectal cancer, KRAS
Prognostic and Diagnostic Value of Spontaneous Tumor-Related Antibodies
Sebastian Kobold,Tim Luetkens,Yanran Cao,Carsten Bokemeyer,Djordje Atanackovic
Clinical and Developmental Immunology , 2010, DOI: 10.1155/2010/721531
Abstract: There is an urgent need for earlier diagnosis of malignancies and more stringent monitoring of relapses after antitumor therapy. In addition, new prognostic markers are needed for risk stratification and design of individualized cancer therapies. New diagnostic and prognostic parameters should overcome the impairments of current standards in a cost-effective manner. Serological approaches measuring spontaneous antibody responses against tumor-associated antigens could be of use as diagnostic and prognostic markers and could also be employed to evaluate response to therapy in cancer patients. Autoantibodies have been suggested to be of frequent and specific occurrence in patients with malignancies and to correlate with clinical parameters. Screening the relevant literature on this topic, we suggest that the analysis of single antibody specificities is unlikely to provide sufficient diagnostic and prognostic accuracy. The combined analysis of autoantibodies targeting different antigens, however, may reach high sensitivity and specificity. In addition, screening cancer patients for autoantibodies might identify subgroups with high relapse risk and a worse prognosis. Larger prospective trials should be initiated to identify sets of tumor-associated autoantibodies suited for the use in diagnostic algorithms for cancer detection and followup.
FLT3 - ITD positive acute lymphocytic leukemia, does it impact on disease′s course?
Sebastian Kobold,Nerbil K?l??,John Scharlau,Carsten Bokemeyer
Turkish Journal of Hematology , 2010,
Abstract:
Prognostic and Diagnostic Value of Spontaneous Tumor-Related Antibodies
Sebastian Kobold,Tim Luetkens,Yanran Cao,Carsten Bokemeyer,Djordje Atanackovic
Journal of Immunology Research , 2010, DOI: 10.1155/2010/721531
Abstract: There is an urgent need for earlier diagnosis of malignancies and more stringent monitoring of relapses after antitumor therapy. In addition, new prognostic markers are needed for risk stratification and design of individualized cancer therapies. New diagnostic and prognostic parameters should overcome the impairments of current standards in a cost-effective manner. Serological approaches measuring spontaneous antibody responses against tumor-associated antigens could be of use as diagnostic and prognostic markers and could also be employed to evaluate response to therapy in cancer patients. Autoantibodies have been suggested to be of frequent and specific occurrence in patients with malignancies and to correlate with clinical parameters. Screening the relevant literature on this topic, we suggest that the analysis of single antibody specificities is unlikely to provide sufficient diagnostic and prognostic accuracy. The combined analysis of autoantibodies targeting different antigens, however, may reach high sensitivity and specificity. In addition, screening cancer patients for autoantibodies might identify subgroups with high relapse risk and a worse prognosis. Larger prospective trials should be initiated to identify sets of tumor-associated autoantibodies suited for the use in diagnostic algorithms for cancer detection and followup. 1. Introduction For close to 150 years, human malignancies and the immune system have been suspected to be interaction partners [1]. While data supporting this relationship has accumulated in recent years, the exact biological role of spontaneously occurring anti-tumor immune responses is still a matter of controversy [2, 3]. In any case, the characterization of the crosstalk between tumors and their immune environment has led to a systematic analysis of the antibody repertoire of cancer patients [4]. The relatively high frequency of spontaneous antibody responses against cancer-related antigens led to the assumption that these antibodies could be of use in the clinical setting [5]. Accordingly, a lot of effort was invested in correlating the presence of such antibodies with clinical parameters to assess their use as prognostic parameters. Furthermore, the highly cancer-specific nature of some of these antibodies resulted in the evaluation of their diagnostic utility [6]. Both approaches seemed very promising as a serological detection of cancer, and a serologic risk stratification would be easy to handle, of low cost, and much more likely to be accepted by a wide majority of patients hesitant to undergo invasive
Cilengitide induces cellular detachment and apoptosis in endothelial and glioma cells mediated by inhibition of FAK/src/AKT pathway
Leticia Oliveira-Ferrer, Jessica Hauschild, Walter Fiedler, Carsten Bokemeyer, Johannes Nippgen, Ilhan Celik, Gunter Schuch
Journal of Experimental & Clinical Cancer Research , 2008, DOI: 10.1186/1756-9966-27-86
Abstract: Cilengitide caused dose-dependent detachment of endothelial cells from cell culture dishes. Proliferation of endothelial cells was significantly inhibited while the proportion of apoptotic cells was increased. Incubation of integrin-expressing glioma cells with cilengitide caused rounding and detachment after 24 hours as observed with endothelial cells. Cilengitide inhibited proliferation and induced apoptosis in glioma cells with methylated MGMT promotor when given alone or in combination with temozolomide. In endothelial as well as glioma cells cilengitide inhibited phosphorylation of FAK, Src and Akt. Assembly of cytoskeleton and tight junctions was heavily disturbed in both cell types.Cilengitide inhibits integrin-dependent signaling, causes disassembly of cytoskeleton, cellular detachment and induction of apoptosis in endothelial and glioma cells thereby explaining the profound activity of integrin inhibitors in gliomas. The combination of cilengitide with temozolomide exerted additive effects in glioma cells as observed clinically.Angiogenesis, the formation of blood vessels from pre-existing vasculature, has been identified as an essential mechanism in tumor growth [1]. This process is mediated by proangiogenic growth factors such as vascular endothelial growth factor (VEGF) inducing proliferation, migration and tube formation of endothelial cells [2]. Another important feature is the interaction of endothelial cells with surrounding extracellular matrix (ECM) that is mediated by integrins. Integrins are transmembrane receptors composed of two subunits binding to ECM and base membrane proteins [3]. Integrin binding mediates adhesion to surrounding structures and regulates cell survival, growth and mobility [4]. Of more than 20 known α/β heterodimers the integrins αvβ3 and αvβ5 are predominantly expressed in proangiogenic endothelial cells [5,6]. A variety of blocking agents and antibodies targeting either one or both integrins has been developed for antiangio
Micro-RNA expression in cisplatin resistant germ cell tumor cell lines
Matthias Port, Stephanie Glaesener, Christian Ruf, Armin Riecke, Carsten Bokemeyer, Viktor Meineke, Friedemann Honecker, Michael Abend
Molecular Cancer , 2011, DOI: 10.1186/1476-4598-10-52
Abstract: Three cisplatin resistant sublines (NTERA-2-R, NCCIT-R, 2102EP-R) showing 2.7-11.3-fold increase in drug resistance after intermittent exposure to increasing doses of cisplatin were compared to their parental counterparts, three well established relatively cisplatin sensitive germ cell tumor cell lines (NTERA-2, NCCIT, 2102EP). Cells were cultured and total RNA was isolated from all 6 cell lines in three independent experiments. RNA was converted into cDNA and quantitative RT-PCR was run using 384 well low density arrays covering almost all (738) known microRNA species of human origin.Altogether 72 of 738 (9.8%) microRNAs appeared differentially expressed between sensitive and resistant cell line pairs (NTERA-2R/NTERA-2 = 43, NCCIT-R/NCCIT = 53, 2102EP-R/2102EP = 15) of which 46.7-95.3% were up-regulated (NTERA-2R/NTERA-2 = 95.3%, NCCIT-R/NCCIT = 62.3%, 2102EP-R/2102EP = 46.7%). The number of genes showing differential expression in more than one of the cell line pairs was 34 between NTERA-2R/NTERA-2 (79%) and NCCIT-R/NCCIT (64%), and 3 and 4, respectively, between these two cell lines and 2102EP-R/2102EP (about 27%). Only the has-miR-10b involved in breast cancer invasion and metastasis and has-miR-512-3p appeared to be up-regulated (2-3-fold) in all three cell lines. The hsa-miR-371-373 cluster (counteracting cellular senescence and linked with differentiation potency), as well as hsa-miR-520c/-520h (inhibiting the tumor suppressor p21) were 3.9-16.3 fold up-regulated in two of the three cisplatin resistant cell lines. Several new micro-RNA species missing an annotation towards cisplatin resistance could be identified. These were hsa-miR-512-3p/-515/-517/-518/-525 (up to 8.1-fold up-regulated) and hsa-miR-99a/-100/-145 (up to 10-fold down-regulated).Examining almost all known human micro-RNA species confirmed the miR-371-373 cluster as a promising target for explaining cisplatin resistance, potentially by counteracting wild-type P53 induced senescence or linking i
Mycalamide A Shows Cytotoxic Properties and Prevents EGF-Induced Neoplastic Transformation through Inhibition of Nuclear Factors
Sergey A. Dyshlovoy,Sergey N. Fedorov,Anatoly I. Kalinovsky,Larisa K. Shubina,Carsten Bokemeyer,Valentin A. Stonik,Friedemann Honecker
Marine Drugs , 2012, DOI: 10.3390/md10061212
Abstract: Mycalamide A, a marine natural compound previously isolated from sponges, is known as a protein synthesis inhibitor with potent antitumor activity. However, the ability of this compound to prevent malignant transformation of cells has never been examined before. Here, for the first time, we report the isolation of mycalamide A from ascidian Polysincraton sp. as well as investigation of its cancer preventive properties. In murine JB6 Cl41 P + cells, mycalamide A inhibited epidermal growth factor (EGF)-induced neoplastic transformation, and induced apoptosis at subnanomolar or nanomolar concentrations. The compound inhibited transcriptional activity of the oncogenic nuclear factors AP-1 and NF-κB, a potential mechanism of its cancer preventive properties. Induction of phosphorylation of the kinases MAPK p38, JNK, and ERK was also observed at high concentrations of mycalamide A. The drug shows promising potential for both cancer-prevention and cytotoxic therapy and should be further developed.
Multi tyrosine kinase inhibitor dasatinib as novel cause of severe pre-capillary pulmonary hypertension?
Jan K Hennigs, Gunhild Keller, Hans Baumann, Friedemann Honecker, Stefan Kluge, Carsten Bokemeyer, Tim H Brümmendorf, Hans Klose
BMC Pulmonary Medicine , 2011, DOI: 10.1186/1471-2466-11-30
Abstract: Here, we discuss the relevance of previously published cases and add another well-characterised patient who developed pre-capillary PH under long-term therapy with the multi-tyrosine kinase inhibitor dasatinib approved for therapy of chronic myeloic leukaemia (CML) and Philadelphia chromosome positive acute lymphocytic leukaemia (mean time of all patients on dasatinib: 26 months). Hence, we discuss the possibility of dasatinib itself causing PH after long-term therapy and turn specialist's attention to this possible severe side effect.At present, the true incidence of dasatinib-associated PH remains illusive and systematic data regarding haemodynamics are missing.We therefore recommend systematic screening of dasatinib-treated patients for pulmonary hypertension and subsequent collection of haemodynamic data.Pulmonary hypertension (PH) is a severe and progressive, mainly vasoproliferative disease characterised by increased pulmonary artery pressure and vascular resistance eventually leading to right heart failure and death [1]. Different drugs have been identified to be causative of PH such as anorectic drugs which gained notoriety in the 1970s [2].Dasatinib is a multi tyrosine kinase inhibitor approved for first and second line therapy of chronic myeloic leukaemia (CML) and Philadelphia chromosome positive acute lymphocytic leukaemia [3,4].During the last months there have been two reports connecting dasatinib with the development of PAH [5,6]. Alarmingly, another patient was referred to our centre presenting with severe pre-capillary PH under dasatinib therapy.Here, we report on this case and would like to turn attention to this possible severe side effect of dasatinib.A 70-year old male with chronic phase CML diagnosed in 1996 was changed to dasatinib therapy due to subsequent haematological progress under hydroxyurea combined with interferon alpha (1996-2002) and imatinib (2002-2004: 400 mg/day, 2004-2005: 800 mg/d). Dasatinib treatment with a dose of 70 mg bid
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