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The oral Multi-Target Tumour Growth Inhibitor™, ZK 304709, inhibits growth of pancreatic neuroendocrine tumours in an orthotopic mouse model
  1. Arne Scholz (arne.scholz{at}charite.de)
  1. Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, CVK, Germany
    1. Karola Wagner (karola.wagner{at}charite.de)
    1. Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, CVK, Germany
      1. Martina Welzel (martina.welzel{at}charite.de)
      1. Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, CVK, Germany
        1. Felix Remlinger (felix_remlinger{at}gmx.de)
        1. Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, CVK, Germany
          1. Bertram Wiedenmann (bertram.wiedenmann{at}charite.de)
          1. Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, CVK, Germany
            1. Gerhard Siemeister (gerhard.siemeister{at}bayerhealthcare.com)
            1. Bayer Schering Pharma AG, Global Drug Discovery, Germany
              1. Stefan Rosewicz (stefan.rosewicz{at}charite.de)
              1. Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, CVK, Germany
                1. Katharina M Detjen (katharina.detjen{at}charite.de)
                1. Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, CVK, Germany

                  Abstract

                  Objective: Current systemic therapies for neuroendocrine tumours (NETs) do not provide sufficient control of tumour growth. However, efficient evaluation of novel drugs is hindered by the lack of a suitable preclinical animal model. Here we establish an orthotopic mouse model of pancreatic NET and use this model to study the action of ZK 304709, a first in class, oral Multi-target Tumour Growth InhibitorTM. ZK 304709 is an inhibitor of Cdks 1, 2, 4, 7 and 9, VEGF-RTKs1-3 and PDGF-RTKβ.

                  Design: BON and QGP-1 human NET cells were used to study proliferation, survival and cell cycle distribution in vitro. For induction of orthotopic NETs, BON cells were injected into the pancreas of NMRInu/nu mice. Primary tumour growth and metastatic spread were recorded after nine weeks and apoptosis, microvessel density and lymphatic vessel density were determined.

                  Results: ZK 304709 dose-dependently suppressed proliferation and colony formation of NET cells. Direct effects on NET cells were consistent with Cdk-inhibition and involved G2-cell cycle arrest and apoptosis induction, which was associated with reduced expression of MCL-1, survivin and HIF-1 α. Apoptosis similarly occurred in vivo in ZK 304709-treated orthotopic BON tumours, resulting in a 80% reduction of primary tumour growth. In contrast, treatment with lanreotide or 5-FU and streptozotocin failed to inhibit tumour gowth. ZK 304709 also reduced tumour microvessel density, implicating antiangiogenic mechanisms.

                  Conclusion: BON orthotopic tumours provide an informative model for preclinical drug evaluation in NETs. In this model, ZK 304709 achieved efficacious tumour growth control via induction of apoptosis and inhibition of tumour-induced angiogenesis.

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