ADAM8 as a drug target in Pancreatic Cancer

Uwe Schlomann; Garrit Koller; Catharina Conrad; Taheera Ferdous; Panagiota Golfi; Adolfo Molejon  Garcia; Sabrina  Hofling; Madeline Parsons; Patricia Costa; Robin  Soper; Maud Bossard; Thorsten Hagemann; Rozita  Roshani; Norbert  Sewald; Randal R. Ketchem; Marcia L. Moss; Fred H.  Rasmussen; Miles A.  Miller; Douglas A.  Lauffenburger; David A. Tuveson; Christopher Nimsky; Joerg Bartsch

doi:10.1038/ncomms7175

ADAM8 as a drug target in Pancreatic Cancer

Uwe Schlomann, Garrit Koller, Catharina Conrad, Taheera Ferdous, Panagiota Golfi, Adolfo Molejon Garcia, Sabrina Hofling, Madeline Parsons, Patricia Costa, Robin Soper, Maud Bossard, Thorsten Hagemann, Rozita Roshani, Norbert Sewald, Randal R. Ketchem, Marcia L. Moss, Fred H. Rasmussen, Miles A. Miller, Douglas A. Lauffenburger, David A. TuvesonChristopher Nimsky, Joerg Bartsch

Research output: Contribution to journal › Article › peer-review

92 Citations (Scopus)

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a grim prognosis with less than 5% survivors after 5 years. High expression levels of ADAM8, a metalloprotease-disintegrin, are correlated with poor clinical outcome. In PDAC cell lines, ADAM8 expression is associated with increased migration and invasiveness caused by activation of ERK 1/2 and higher MMP activities. For biological function, ADAM8 requires multimerisation 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 multimerisation. In PDAC cell lines, BK-1361 affects ADAM8 function leading to reduced invasiveness, and less ERK 1/2 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 KrasG12D-driven mouse model of PDAC. Thus, our data integrate ADAM8 in pancreatic cancer signalling and validate ADAM8 as a target for PDAC therapy.

Original language	English
Article number	6175
Number of pages	15
Journal	Nature Communications
Volume	6
Issue number	1
Early online date	28 Jan 2015
DOIs	https://doi.org/10.1038/ncomms7175
Publication status	Published - 28 Jan 2015

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/ncomms7175

Cite this

Schlomann, U., Koller, G., Conrad, C., Ferdous, T., Golfi, P., Garcia, A. M., Hofling, S., Parsons, M., Costa, P., Soper, R., Bossard, M., Hagemann, T., Roshani, R., Sewald, N., Ketchem, R. R., Moss, M. L., Rasmussen, F. H., Miller, M. A., Lauffenburger, D. A., ... Bartsch, J. (2015). ADAM8 as a drug target in Pancreatic Cancer. Nature Communications, 6(1), Article 6175. https://doi.org/10.1038/ncomms7175

@article{37a97ffea5d845bead5663567592916b,

title = "ADAM8 as a drug target in Pancreatic Cancer",

abstract = "Pancreatic ductal adenocarcinoma (PDAC) has a grim prognosis with less than 5% survivors after 5 years. High expression levels of ADAM8, a metalloprotease-disintegrin, are correlated with poor clinical outcome. In PDAC cell lines, ADAM8 expression is associated with increased migration and invasiveness caused by activation of ERK 1/2 and higher MMP activities. For biological function, ADAM8 requires multimerisation 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 multimerisation. In PDAC cell lines, BK-1361 affects ADAM8 function leading to reduced invasiveness, and less ERK 1/2 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 KrasG12D-driven mouse model of PDAC. Thus, our data integrate ADAM8 in pancreatic cancer signalling and validate ADAM8 as a target for PDAC therapy.",

author = "Uwe Schlomann and Garrit Koller and Catharina Conrad and Taheera Ferdous and Panagiota Golfi and Garcia, {Adolfo Molejon} and Sabrina Hofling and Madeline Parsons and Patricia Costa and Robin Soper and Maud Bossard and Thorsten Hagemann and Rozita Roshani and Norbert Sewald and Ketchem, {Randal R.} and Moss, {Marcia L.} and Rasmussen, {Fred H.} and Miller, {Miles A.} and Lauffenburger, {Douglas A.} and Tuveson, {David A.} and Christopher Nimsky and Joerg Bartsch",

year = "2015",

month = jan,

day = "28",

doi = "10.1038/ncomms7175",

language = "English",

volume = "6",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Schlomann, U , Koller, G, Conrad, C, Ferdous, T, Golfi, P, Garcia, AM, Hofling, S, Parsons, M , Costa, P, Soper, R, Bossard, M, Hagemann, T, Roshani, R, Sewald, N, Ketchem, RR, Moss, ML, Rasmussen, FH, Miller, MA, Lauffenburger, DA, Tuveson, DA, Nimsky, C & Bartsch, J 2015, 'ADAM8 as a drug target in Pancreatic Cancer', Nature Communications, vol. 6, no. 1, 6175. https://doi.org/10.1038/ncomms7175

TY - JOUR

T1 - ADAM8 as a drug target in Pancreatic Cancer

AU - Schlomann, Uwe

AU - Koller, Garrit

AU - Conrad, Catharina

AU - Ferdous, Taheera

AU - Golfi, Panagiota

AU - Garcia, Adolfo Molejon

AU - Hofling, Sabrina

AU - Parsons, Madeline

AU - Costa, Patricia

AU - Soper, Robin

AU - Bossard, Maud

AU - Hagemann, Thorsten

AU - Roshani, Rozita

AU - Sewald, Norbert

AU - Ketchem, Randal R.

AU - Moss, Marcia L.

AU - Rasmussen, Fred H.

AU - Miller, Miles A.

AU - Lauffenburger, Douglas A.

AU - Tuveson, David A.

AU - Nimsky, Christopher

AU - Bartsch, Joerg

PY - 2015/1/28

Y1 - 2015/1/28

N2 - Pancreatic ductal adenocarcinoma (PDAC) has a grim prognosis with less than 5% survivors after 5 years. High expression levels of ADAM8, a metalloprotease-disintegrin, are correlated with poor clinical outcome. In PDAC cell lines, ADAM8 expression is associated with increased migration and invasiveness caused by activation of ERK 1/2 and higher MMP activities. For biological function, ADAM8 requires multimerisation 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 multimerisation. In PDAC cell lines, BK-1361 affects ADAM8 function leading to reduced invasiveness, and less ERK 1/2 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 KrasG12D-driven mouse model of PDAC. Thus, our data integrate ADAM8 in pancreatic cancer signalling and validate ADAM8 as a target for PDAC therapy.

AB - Pancreatic ductal adenocarcinoma (PDAC) has a grim prognosis with less than 5% survivors after 5 years. High expression levels of ADAM8, a metalloprotease-disintegrin, are correlated with poor clinical outcome. In PDAC cell lines, ADAM8 expression is associated with increased migration and invasiveness caused by activation of ERK 1/2 and higher MMP activities. For biological function, ADAM8 requires multimerisation 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 multimerisation. In PDAC cell lines, BK-1361 affects ADAM8 function leading to reduced invasiveness, and less ERK 1/2 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 KrasG12D-driven mouse model of PDAC. Thus, our data integrate ADAM8 in pancreatic cancer signalling and validate ADAM8 as a target for PDAC therapy.

U2 - 10.1038/ncomms7175

DO - 10.1038/ncomms7175

M3 - Article

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 6175

ER -

ADAM8 as a drug target in Pancreatic Cancer

Abstract

UN SDGs

Access to Document

Fingerprint

Cite this