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Combination of Hedgehog Signaling Blockage and Chemotherapy Leads to Tumor Reduction in Pancreatic Adenocarcinomas

Bahra, Marcus MD, PhD*; Kamphues, Carsten MD*; Boas-Knoop, Sabine VMD*; Lippert, Steffen MLS*; Esendik, Ulrike MLS; Schüller, Ulrich MD, PhD; Hartmann, Wolfgang MD, PhD§; Waha, Andreas PhD; Neuhaus, Peter MD, PhD*; Heppner, Frank MD, PhD; Pietsch, Torsten MD, PhD; Koch, Arend MD, PhD

doi: 10.1097/MPA.0b013e31822896dd
Original Articles
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Objectives Activation of the hedgehog signal transduction pathway, triggered by hedgehog binding to the transmembrane receptor patched 1 (PTCH1) or by mutations in the PTCH1 gene, plays an important role in the development of various tumors.

Methods To investigate whether the Hedgehog signaling pathway is also active in human pancreatic adenocarcinomas, we determined the expression levels of the known Hedgehog target genes PTCH1 and GLI-1 in pancreatic tumors. To determine whether alterations in the PTCH1 gene are responsible for this pathway activation, we screened pancreatic carcinomas for mutations in PTCH. To investigate the contribution of hedgehog signaling to the tumorigenicity of pancreatic tumor cells, we blocked the Hedgehog pathway in cultured tumor cells and xenografts using the steroidal alkaloid cyclopamine and the small-molecule Hedgehog inhibitor Hh-Antag.

Results We identified single nucleotide polymorphisms (SNPs) within the PTCH1 gene but no somatic PTCH1 mutations. Pathway-blockage resulted in a significant dose-dependent reduction of tumor cell growth in vitro and in vivo. Moreover, combined treatment with cyclopamine and the conventional antimetabolite gemcitabine revealed a synergistic effect on the reduction of tumor growth in pancreatic adenocarcinoma xenografts.

Conclusions Inhibition of Hedgehog signaling could be a promising approach for the treatment of pancreatic adenocarcinomas.

From the *Department of General, Visceral and Transplantation Surgery, Charité Universitätsmedizin Berlin, Berlin; †Department of Neuropathology, University of Bonn, Bonn; ‡Department of Neuropathology, Ludwig-Maximilians University Munich, Munich; §Department of Pathology, University of Bonn, Bonn; and ∥Department of Neuropathology, Charité Universitätsmedizin Berlin, Berlin, Germany.

Received for publication April 13, 2011; accepted May 18, 2011.

Reprints: Marcus Bahra, MD, PhD, Department of General, Visceral and Transplantation Surgery; Arend Koch, MD, PhD, Department of Neuropathology, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin D-13353, Germany (e-mail: marcus.bahra@charite.de).

The authors declare no conflict of interest.

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