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Hedgehog inhibition prolongs survival in a genetically engineered mouse model of pancreatic cancer
  1. Georg Feldmann (gfeldma4{at}jhmi.edu)
  1. Johns Hopkins University, United States
    1. Nils Habbe (nhabbe2{at}jhmi.edu)
    1. Johns Hopkins University, United States
      1. Surajit Dhara (sdhara1{at}jhmi.edu)
      1. Johns Hopkins University, United States
        1. Savita Bisht (sbisht1{at}jhmi.edu)
        1. Johns Hopkins University, United States
          1. Hector Alvarez (halvare1{at}jhmi.edu)
          1. Johns Hopkins University, United States
            1. Volker Fendrich (fendrich{at}med.uni-marburg.de)
            1. Philipps-Universitaet Marburg, Germany
              1. Robert Beaty (rbeaty1{at}jhmi.edu)
              1. Johns Hopkins University, United States
                1. Michael Mullendore (mmullen7{at}jhmi.edu)
                1. Johns Hopkins University, United States
                  1. Collins Karikari (ckarika1{at}jhmi.edu)
                  1. Johns Hopkins University, United States
                    1. nabeel Bardeesy (bardeesy.nabeel{at}mgh.harvard.edu)
                    1. Harvard Medical School, United States
                      1. Michel M. Oullette (mouellet3{at}yahoo.com)
                      1. University of Nebraska Medical Center, United States
                        1. Wayne Yu (wyu8{at}jhmi.edu)
                        1. Johns Hopkins University, United States
                          1. Anirban Maitra (amaitra1{at}jhmi.edu)
                          1. Johns Hopkins University, United States

                            Abstract

                            Background and aims: Pancreatic cancer is among the most dismal of human malignancies. Current therapeutic strategies are virtually ineffective in controlling advanced, metastatic disease. Recent evidence suggests that the Hedgehog signaling pathway is aberrantly reactivated in the majority of pancreatic cancers, and that Hedgehog blockade has the potential to prevent disease progression and metastatic spread.

                            Methods: Here we show that the Hedgehog pathway is activated in the Pdx1-Cre; LsL-KrasG12D; Ink4a/Arflox/lox transgenic mouse model of pancreatic cancer. The effect of Hedgehog pathway inhibition on survival was determined by continuous application of the small molecule smoothened antagonist cyclopamine. Microarray analysis was performed on non-malignant human pancreatic ductal cells overexpressing Gli1 in order to screen for downstream Hedgehog target genes likely involved in pancreatic cancer progression.

                            Results: Hedgehog inhibition with cyclopamine significantly prolonged median survival in the used transgenic mouse model (67 vs. 61 days; p=0.026). In vitro data indicated that Hedgehog-activation might at least in part be ascribed to oncogenic Kras signaling. Microarray analysis identified 26 potential Hedgehog target genes that had previously been found to be overexpressed in pancreatic cancer. Five of them, BIRC3, COL11A1, NNMT, PLAU and TGM2 had been described as upregulated in more than one global gene expression analysis before.

                            Conclusion: This study provides another line of evidence, that Hedgehog signaling is a valid target for the development of novel therapeutics for pancreatic cancer that might be worth soon to be evaluated in a clinical setting.

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