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Freiburg, Germany

Easmon J.,University of Innsbruck | Purstinger G.,University of Innsbruck | Heinisch G.,University of Innsbruck | Fiebig H.H.,Oncotest | And 2 more authors.
Archiv der Pharmazie | Year: 2014

A series of 2-pyridylhydrazones derived from phenyl-pyridazin-3-yl- methanones were prepared in search for potential novel antitumor agents. The stereochemistry of these compounds was established by means of NMR spectroscopy. Whereas hydrazones derived from 3-benzoylpyridazines (IC50 = 0.99-8.74 μM) inhibited the proliferation of the tumor cell lines tested, the non-fully aromatic 3-benzoylpyridazinone hydrazones (IC50 > 10 μM) turned out to be inactive. Compounds E-1b (IC50 = 0.12 μM) and E-1d (IC50 = 0.18 μM) exert high cytotoxic activities in clonogenic assays involving human tumor cells of different tissue origins. In vivo application of compound E-1b (300 mg/kg/day) resulted in a 66% reduction in tumor burden.© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Forest A.,Eli Lilly and Company | Amatulli M.,Eli Lilly and Company | Ludwig D.L.,Eli Lilly and Company | Damoci C.B.,Eli Lilly and Company | And 12 more authors.
Molecular Cancer Research | Year: 2015

Despite a recent shift away from anti-insulin-like growth factor I receptor (IGF-IR) therapy, this target has been identified as a key player in the resistance mechanisms to various conventional and targeted agents, emphasizing its value as a therapy, provided that it is used in the right patient population. Molecular markers predictive of antitumor activity of IGF-IR inhibitors remain largely unidentified. The aim of this study is to evaluate the impact of insulin receptor (IR) isoforms on the antitumor efficacy of cixutumumab, a humanized mAb against IGF-IR, and to correlate their expression with therapeutic outcome. The data demonstrate that expression of total IR rather than individual IR isoforms inversely correlates with single-Agent cixutumumab efficacy in pediatric solid tumor models in vivo. Total IR, IR-A, and IR-B expression adversely affects the outcome of cixutumumab in combination with chemotherapy in patient-derived xenograft models of lung adenocarcinoma. IR-A overexpression in tumor cells confers complete resistance to cixutumumab in vitro and in vivo, whereas IR-B results in a partial resistance. Resistance in IRB- overexpressing cells is fully reversed by anti-IGF-II antibodies, suggesting that IGF-II is a driver of cixutumumab resistance in this setting. The present study links IR isoforms, IGF-II, and cixutumumab efficacy mechanistically and identifies total IR as a biomarker predictive of intrinsic resistance to anti-IGF-IR antibody. Implications: This study identifies total IRasabiomarker predictive of primary resistance to IGF-IR antibodies and provides a rationale for new clinical trials enriched for patients whose tumors display low IR expression. © 2015 American Association for Cancer Research.

Schueler J.,Albert Ludwigs University of Freiburg | Wider D.,Albert Ludwigs University of Freiburg | Klingner K.,Oncotest | Siegers G.M.,University of Western Ontario | And 4 more authors.
PLoS ONE | Year: 2013

Background: We systematically analyzed multiple myeloma (MM) cell lines and patient bone marrow cells for their engraftment capacity in immunodeficient mice and validated the response of the resulting xenografts to antimyeloma agents. Design and Methods: Using flow cytometry and near infrared fluorescence in-vivo-imaging, growth kinetics of MM cell lines L363 and RPMI8226 and patient bone marrow cells were investigated with use of a murine subcutaneous bone implant, intratibial and intravenous approach in NOD/SCID, NOD/SCID treated with CD122 antibody and NOD/ SCID IL-2Rγ(null) mice (NSG). Results: Myeloma growth was significantly increased in the absence of natural killer cell activity (NSG or αCD122-treated NOD/SCID). Comparison of NSG and áCD122-treated NOD/SCID revealed enhanced growth kinetics in the former, especially with respect to metastatic tumor sites which were exclusively observed therein. In NSG, MM cells were more tumorigenic when injected intratibially than intravenously. In NOD/SCID in contrast, the use of juvenile long bone implants was superior to intratibial or intravenous cancer cell injection. Using the intratibial NSG model, mice developed typical disease symptoms exclusively when implanted with human MM cell lines or patient-derived bone marrow cells, but not with healthy bone marrow cells nor in mock-injected animals. Bortezomib and dexamethasone delayed myeloma progression in L363- as well as patient-derived MM cell bearing NSG. Antitumor activity could be quantified via flow cytometry and in vivo imaging analyses. Conclusions: Our results suggest that the intratibial NSG MM model mimics the clinical situation of the disseminated disease and serves as a valuable tool in the development of novel anticancer strategies. © 2013 Schueler et al.

Sung V.,Celgene | Richard N.,Celgene | Brady H.,Celgene | Maier A.,Oncotest | And 2 more authors.
Cancer Science | Year: 2011

Histone deacetylase inhibitors are a group of recently developed compounds that modulate cell growth and survival. We evaluated the effects of the histone deacetylase inhibitor MGCD0103 on growth of pancreatic carcinoma models following single agent treatment and in combination with gemcitabine. MGCD0103 inhibited tumor cell growth and acted synergistically with gemcitabine to enhance its cytotoxic effects. Gene expression analysis identified the cell cycle pathway as one of the most highly modulated gene groups. Our data suggest that MGCD0103+gemcitabine might be an effective treatment for gemcitabine-refractory pancreatic cancer. © 2011 Japanese Cancer Association.

Lee J.Y.,Sungkyunkwan University | Kim S.Y.,Sungkyunkwan University | Park C.,Sungkyunkwan University | Kim N.K.D.,Samsung | And 25 more authors.
Oncotarget | Year: 2015

Background: In this study, we established patient-derived tumor cell (PDC) models using tissues collected from patients with metastatic cancer and assessed whether these models could be used as a tool for genome-based cancer treatment. Methods: PDCs were isolated and cultured from malignant effusions including ascites and pleural fluid. Pathological examination, immunohistochemical analysis, and genomic profiling were performed to compare the histological and genomic features of primary tumors, PDCs. An exploratory gene expression profiling assay was performed to further characterize PDCs. Results: From January 2012 to May 2013, 176 samples from patients with metastatic cancer were collected. PDC models were successfully established in 130 (73.6%) samples. The median time from specimen collection to passage 1 (P1) was 3 weeks (range, 0.5-4 weeks), while that from P1 to P2 was 2.5 weeks (range, 0.5-5 weeks). Sixteen paired samples of genomic alterations were highly concordant between each primary tumor and progeny PDCs, with an average variant allele frequency (VAF) correlation of 0.878. We compared genomic profiles of the primary tumor (P0), P1 cells, P2 cells, and patient-derived xenografts (PDXs) derived from P2 cells and found that three samples (P0, P1, and P2 cells) were highly correlated (0.99-1.00). Moreover, PDXs showed more than 100 variants, with correlations of only 0.6-0.8 for the other samples. Drug responses of PDCs were reflective of the clinical response to targeted agents in selected patient PDC lines. Conclusion(s): Our results provided evidence that our PDC model was a promising model for preclinical experiments and closely resembled the patient tumor genome and clinical response.

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