New Xenografts Study Findings Have Been Reported by Researchers at Aarhus University (Indirect targeting of IGF receptor signaling in vivo by substrate-selective inhibition of PAPP-A proteolytic activity)
By a News Reporter-Staff News Editor at Clinical Trials Week -- Investigators publish new report on Biotechnology. According to news reporting originating from Aarhus, Denmark, by NewsRx correspondents, research stated, "The insulin-like growth factor (IGF) signaling pathway is involved in certain human cancers, and the feasibility of directly targeting the IGF receptor has been actively investigated. However, recent evidence from clinical trials suggests that this approach can be problematic."
Our news editors obtained a quote from the research from Aarhus University, "We have developed an alternative strategy to indirectly inhibit the IGF signaling by targeting the metalloproteinase, pregnancy-associated plasma protein-A (PAPP-A). PAPP-A associated with the cell surface cleaves IGF binding protein-4 (IGFBP-4), when IGF is bound to IGFBP-4, and thereby increases IGF bioavailability for receptor activation in an autocrine/paracrine manner. We hypothesized that inhibition of PAPP-A would suppress excessive local IGF signaling in tissues where this is caused by increased PAPP-A proteolytic activity. To test this hypothesis, we developed an inhibitory monoclonal antibody, mAb 1/41, which targets a unique substrate-binding exosite of PAPP-A. This inhibitor selectively and specifically inhibits proteolytic cleavage of IGFBP-4 with an inhibitory constant (Ki) of 135 pM. In addition, it inhibited intracellular signaling of the IGF receptor (AKT phosphorylation) in monolayers of A549 cells, an IGF-responsive lung cancer-derived cell line found to express high levels of PAPP-A. We further showed that mAb 1/41 is effective towards PAPP-A bound to cell surfaces, and that it is capable of inhibiting PAPP-A activity in vivo. Using a murine xenograft model of A549 cells, we demonstrated that mAb 1/41 administered intraperitoneally significantly inhibited tumor growth. Analysis of xenograft tumor tissue recovered from treated mice showed penetration of mAb 1/41, reduced IGFBP-4 proteolysis, and reduced AKT phosphorylation. Our study provides proof of concept that IGF signaling can be selectively reduced by targeting a regulatory proteinase that functions extracellularly, upstream of the IGF receptor."
According to the news editors, the research concluded: "PAPP-A targeting thus represents an alternative therapeutic strategy for inhibiting IGF receptor signaling."
For more information on this research see: Indirect targeting of IGF receptor signaling in vivo by substrate-selective inhibition of PAPP-A proteolytic activity. Oncotarget, 2014;5(4):1014-25 (see also Biotechnology).
The news editors report that additional information may be obtained by contacting J.H. Mikkelsen, Dept. of Molecular Biology and Genetics, University of Aarhus, DK-8000 Aarhus C, Denmark. Additional authors for this research include Z.T. Resch, B. Kalra, G. Savjani, A. Kumar, C.A. Conover and C. Oxvig.
Keywords for this news article include: Biotechnology, Aarhus, Europe, Denmark, Xenograft, Xenotransplantion.
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