Showing papers by "Axel Ullrich published in 2016"
TL;DR: The anti-tumoral effect of small molecule inhibitor BMS-777607 targeting RTK-AXL in a preclinical glioma model and evidence that RTK -AXL is expressed and phosphorylated in primary and recurrent glioblastoma multiforme (GBM) are suggested.
Abstract: // Julia Onken 1 , Robert Torka 3 , Soren Korsing 1 , Josefine Radke 2 , Irina Krementeskaia 1 , Melina Nieminen 1 , Xi Bai 1 , Axel Ullrich 3 , Frank Heppner 2 , Peter Vajkoczy 1 1 Department of Neurosurgery, Charite, Berlin, Germany 2 Institute of Neuropathology, Charite, Berlin, Germany 3 Department of Molecular Biology, Max-Planck Institute of Biochemistry, Martinsried, Germany Correspondence to: Peter Vajkoczy, e-mail: peter.vajkoczy@charite.de Keywords: glioblastoma multiforme (GBM), small molecule inhibitor BMS-777607, receptor tyrosine kinase AXL (RTK-AXL), invasion, xenograft model Received: October 20, 2015 Accepted: January 19, 2016 Published: February 02, 2016 ABSTRACT Purpose: Receptor tyrosine kinase AXL (RTK-AXL) is regarded as suitable target in glioma therapy. Here we evaluate the anti-tumoral effect of small molecule inhibitor BMS-777607 targeting RTK-AXL in a preclinical glioma model and provide evidence that RTK-AXL is expressed and phosphorylated in primary and recurrent glioblastoma multiforme (GBM). Experimental design: We studied the impact of BMS-777607 targeting RTK-AXL in GBM models in vitro and in vivo utilizing glioma cells SF126 and U118MG. Impact on proliferation, apoptosis and angiogenesis was investigated by immunohistochemistry (IHC) and functional assays in vitro and in vivo . Tumor growth was assessed with MRI. Human GBM tissue was analyzed in terms of RTK-AXL phosphorylation by immunoprecipitation and immunohistochemistry. Results: BMS-777607 displayed various anti-cancer effects dependent on increased apoptosis, decreased proliferation and migration in vitro and ex vivo in SF126 and U118 GBM cells. In vivo we observed a 56% tumor volume reduction in SF126 xenografts and remission in U118MG xenografts of more than 91%. The tube formation assay confirmed the anti-angiogenic effect of BMS-777607, which became also apparent in tumor xenografts. IHC of human GBM tissue localized phosphorylated RTK-AXL in hypercellular tumor regions, the migratory front of tumor cells in pseudo-palisades, and in vascular proliferates within the tumor. We further proved RTK-AXL phosphorylation in primary and recurrent disease state. Conclusion: Collectively, these data strongly suggest that targeting RTK-AXL with BMS-777607 could represent a novel and potent regimen for the treatment of primary and recurrent GBM.
41 citations
TL;DR: It is found that salinomycin induces an additional cytotoxic effect by inhibiting the ligand independent activation of ERα that leads to a premature fusion of endosomes with lysosomes and thus to the degradation of Egfr family members in luminal A breast cancer cell lines.
Abstract: // Ann-Katrin Sommer 1, 2 , Adam Hermawan 1 , Frauke Martina Mickler 3 , Bojan Ljepoja 1 , Pjotr Knyazev 2 , Christoph Brauchle 3 , Axel Ullrich 2 , Ernst Wagner 1 , Andreas Roidl 1 1 Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universitat Munchen, 81377 Munich, Germany 2 Department of Molecular Biology, Max-Planck-Institute of Biochemistry, 82152 Martinsried, Germany 3 Physical Chemistry, Department of Chemistry, Ludwig-Maximilians-Universitat Munchen, 81377 Munich, Germany Correspondence to: Andreas Roidl, email: andreas.roidl@cup.uni-muenchen.de Keywords: tamoxifen, resistance, salinomycin, endosomal trafficking, breast cancer Received: February 3, 2016 Accepted: June 17, 2016 Published: July 07, 2016 ABSTRACT Luminal A breast cancer is the most common breast cancer subtype which is usually treated with selective estrogen receptor modulators (SERMS) like tamoxifen. Nevertheless, one third of estrogen receptor positive breast cancer patients initially do not respond to endocrine therapy and about 40% of luminal A breast tumors recur in five years. In this study, we investigated an alternative treatment approach by combining tamoxifen and salinomycin in luminal A breast cancer cell lines. We have found that salinomycin induces an additional cytotoxic effect by inhibiting the ligand independent activation of ERα. Thereby salinomycin increases the intracellular calcium level. This leads to a premature fusion of endosomes with lysosomes and thus to the degradation of Egfr family members. Since this process is essential for luminal A breast cancer cells to circumvent tamoxifen treatment, the combination of both drugs induces cytotoxicity in tamoxifen sensitive as well as resistant luminal A breast cancer cell lines.
15 citations
TL;DR: A series of novel pyrido[2,3-d]pyrimidin-7-one derivatives were synthesized as potential antidiabetic agents, preventing IRS-1 phosphorylation at serine 307 in a cellular model of lipotoxicity and type 2 diabetes.
11 citations
TL;DR: It is reported that germline mutations in the membrane-proximal region of type I receptors are able to modulate the amplitude of signal transducer and activator of transcription 3 (STAT3) signaling in cells.
Abstract: In cancer biology, somatic mutations in the extracellular (ligand binding) and cytosolic (functional/catalytic) domains are pursued with great interest. However, in our recent publication we report that germline mutations in the membrane-proximal region of type I receptors are able to modulate the amplitude of signal transducer and activator of transcription 3 (STAT3) signaling in cells. This unexpected finding has implications for the prognosis of heritable cancer.
7 citations