2. Academic Validation
  3. ADAM8 as a drug target in pancreatic cancer

ADAM8 as a drug target in pancreatic cancer

  • Nat Commun. 2015 Jan 28;6:6175. doi: 10.1038/ncomms7175.
Uwe Schlomann 1,  Garrit Koller 2,  Catharina Conrad 3,  Taheera Ferdous 2,  Panagiota Golfi 2,  Adolfo Molejon Garcia 2,  Sabrina Höfling 2,  Maddy Parsons 4,  Patricia Costa 5,  Robin Soper 5,  Maud Bossard 5,  Thorsten Hagemann 5,  Rozita Roshani 5,  Norbert Sewald 6,  Randal R Ketchem 7,  Marcia L Moss 8,  Fred H Rasmussen 8,  Miles A Miller 9,  Douglas A Lauffenburger 9,  David A Tuveson 10,  Christopher Nimsky 3,  Jörg W Bartsch 1
Affiliations

Affiliations

  • 1 1] King's College London, Institute for Pharmaceutical Science and KCLDI, London SE1 9RT, UK [2] Department of Neurosurgery, Marburg University, , Baldingerstrasse, 35033 Marburg, Germany.
  • 2 King's College London, Institute for Pharmaceutical Science and KCLDI, London SE1 9RT, UK.
  • 3 Department of Neurosurgery, Marburg University, , Baldingerstrasse, 35033 Marburg, Germany.
  • 4 King's College London, Randall Institute, London SE1 8RT, UK.
  • 5 Institute of Cancer and Inflammation, St Mary's School of Medicine, John Vane Building, Charterhouse Square, London, EC1M 6BQ, UK.
  • 6 Department of Organic Chemistry, Bielefeld University, 33615 Bielefeld, Germany.
  • 7 Therapeutic Discovery, AMGEN Inc., Seattle, Washington 98119, USA.
  • 8 Biozyme Inc., Apex, North Carolina 27523, USA.
  • 9 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
  • 10 Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11791, USA.
PMID: 25629724 DOI: 10.1038/ncomms7175
Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a grim prognosis with <5% survivors after 5 years. High expression levels of ADAM8, a metalloprotease disintegrin, are correlated with poor clinical outcome. We show that ADAM8 expression is associated with increased migration and invasiveness of PDAC cells caused by activation of ERK1/2 and higher MMP activities. For biological function, ADAM8 requires multimerization and associates with β1 Integrin on the cell surface. A peptidomimetic ADAM8 Inhibitor, BK-1361, designed by structural modelling of the disintegrin domain, prevents ADAM8 multimerization. In PDAC cells, BK-1361 affects ADAM8 function leading to reduced invasiveness, and less ERK1/2 and MMP activation. BK-1361 application in mice decreased tumour burden and metastasis of implanted pancreatic tumour cells and provides improved metrics of clinical symptoms and survival in a Kras(G12D)-driven mouse model of PDAC. Thus, our data integrate ADAM8 in pancreatic Cancer signalling and validate ADAM8 as a target for PDAC therapy.

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