Article Text

Download PDFPDF
Hedgehog inhibition prolongs survival in a genetically engineered mouse model of pancreatic cancer
  1. G Feldmann1,
  2. N Habbe1,
  3. S Dhara1,2,
  4. S Bisht1,
  5. H Alvarez1,
  6. V Fendrich3,4,
  7. R Beaty1,5,
  8. M Mullendore1,
  9. C Karikari1,
  10. N Bardeesy6,
  11. M M Ouellette7,
  12. W Yu8,
  13. A Maitra1
  1. 1
    Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  2. 2
    Department of Radiology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  3. 3
    Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  4. 4
    Department of Surgery, Philipps-Universitaet, Marburg, Germany
  5. 5
    Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  6. 6
    Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA
  7. 7
    Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, New England, USA
  8. 8
    DNA Microarray Core Facility, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  1. Dr G Feldmann, Department of Pathology, Johns Hopkins University School of Medicine, Cancer Research Building II, Room 316, 1550 Orleans Street, Baltimore, MD 21210, USA; gfeldma4{at}jhmi.edu

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 signalling 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 it is shown 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 cyclopamine, a smoothened antagonist. Microarray analysis was performed on non-malignant human pancreatic ductal cells overexpressing Gli1 in order to screen for downstream Hedgehog target genes likely to be involved in pancreatic cancer progression.

Results: Hedgehog inhibition with cyclopamine significantly prolonged median survival in the transgenic mouse model used here (67 vs 61 days; p = 0.026). In vitro data indicated that Hedgehog activation might at least in part be ascribed to oncogenic Kras signalling. 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 signalling is a valid target for the development of novel therapeutics for pancreatic cancer that might be worth evaluating soon in a clinical setting.

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Footnotes

  • ▸ Additional methods, a figure and a table are published online only at http://gut.bmj.com/content/vol57/issue10

  • Funding: Supported by the Sol Goldman Pancreatic Cancer Research Center, the Michael Rolfe Foundation, NIH SPORE (Specialized Programs of Research Excellence) in Gastrointestinal Cancer P50CA62924 and NIH R01CA113669 to AM. GF was supported by a fellowship grant within the postdoc-programme of the German Academic Exchange Service (DAAD). HA received generous support from the D’Amato Family.

  • Competing interests: None.