Therapeutic efficacy of anti-MMP9 antibody in combination with nab-paclitaxel-based chemotherapy in pre-clinical models of pancreatic cancer

Niranjan Awasthi, Amanda J. Mikels-Vigdal, Erin Stefanutti, Margaret Schwarz, Sheena Monahan, Victoria Smith, Roderich E. Schwarz

Research output: Contribution to journalArticle

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Abstract

Matrix metalloproteinase 9 (MMP9) is involved in the proteolysis of extracellular proteins and plays a critical role in pancreatic ductal adenocarcinoma (PDAC) progression, invasion and metastasis. The therapeutic potential of an anti-MMP9 antibody (αMMP9) was evaluated in combination with nab-paclitaxel (NPT)-based standard cytotoxic therapy in pre-clinical models of PDAC. Tumour progression and survival studies were performed in NOD/SCID mice. The mechanistic evaluation involved RNA-Seq, Luminex, IHC and Immunoblot analyses of tumour samples. Median animal survival compared to controls was significantly increased after 2-week therapy with NPT (59%), Gem (29%) and NPT+Gem (76%). Addition of αMMP9 antibody exhibited further extension in survival: NPT+αMMP9 (76%), Gem+αMMP9 (47%) and NPT+Gem+αMMP9 (94%). Six-week maintenance therapy revealed that median animal survival was significantly increased after NPT+Gem (186%) and further improved by the addition of αMMP9 antibody (218%). Qualitative assessment of mice exhibited that αMMP9 therapy led to a reduction in jaundice, bloody ascites and metastatic burden. Anti-MMP9 antibody increased the levels of tumour-associated IL-28 (1.5-fold) and decreased stromal markers (collagen I, αSMA) and the EMT marker vimentin. Subcutaneous tumours revealed low but detectable levels of MMP9 in all therapy groups but no difference in MMP9 expression. Anti-MMP9 antibody monotherapy resulted in more gene expression changes in the mouse stroma compared to the human tumour compartment. These findings suggest that anti-MMP9 antibody can exert specific stroma-directed effects that could be exploited in combination with currently used cytotoxics to improve clinical PDAC therapy.

Original languageEnglish (US)
Pages (from-to)3878-3887
Number of pages10
JournalJournal of Cellular and Molecular Medicine
Volume23
Issue number6
DOIs
StatePublished - Jun 1 2019

Fingerprint

Matrix Metalloproteinase 9
Pancreatic Neoplasms
Drug Therapy
Antibodies
Therapeutics
Adenocarcinoma
Neoplasms
130-nm albumin-bound paclitaxel
Inbred NOD Mouse
SCID Mice
Survival
Vimentin
Group Psychotherapy
Jaundice
Ascites
Proteolysis
Collagen

Keywords

  • combination therapy
  • gemcitabine
  • MMP9
  • nab-paclitaxel
  • pancreatic cancer

ASJC Scopus subject areas

  • Molecular Medicine
  • Cell Biology

Cite this

Therapeutic efficacy of anti-MMP9 antibody in combination with nab-paclitaxel-based chemotherapy in pre-clinical models of pancreatic cancer. / Awasthi, Niranjan; Mikels-Vigdal, Amanda J.; Stefanutti, Erin; Schwarz, Margaret; Monahan, Sheena; Smith, Victoria; Schwarz, Roderich E.

In: Journal of Cellular and Molecular Medicine, Vol. 23, No. 6, 01.06.2019, p. 3878-3887.

Research output: Contribution to journalArticle

Awasthi, Niranjan ; Mikels-Vigdal, Amanda J. ; Stefanutti, Erin ; Schwarz, Margaret ; Monahan, Sheena ; Smith, Victoria ; Schwarz, Roderich E. / Therapeutic efficacy of anti-MMP9 antibody in combination with nab-paclitaxel-based chemotherapy in pre-clinical models of pancreatic cancer. In: Journal of Cellular and Molecular Medicine. 2019 ; Vol. 23, No. 6. pp. 3878-3887.
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abstract = "Matrix metalloproteinase 9 (MMP9) is involved in the proteolysis of extracellular proteins and plays a critical role in pancreatic ductal adenocarcinoma (PDAC) progression, invasion and metastasis. The therapeutic potential of an anti-MMP9 antibody (αMMP9) was evaluated in combination with nab-paclitaxel (NPT)-based standard cytotoxic therapy in pre-clinical models of PDAC. Tumour progression and survival studies were performed in NOD/SCID mice. The mechanistic evaluation involved RNA-Seq, Luminex, IHC and Immunoblot analyses of tumour samples. Median animal survival compared to controls was significantly increased after 2-week therapy with NPT (59{\%}), Gem (29{\%}) and NPT+Gem (76{\%}). Addition of αMMP9 antibody exhibited further extension in survival: NPT+αMMP9 (76{\%}), Gem+αMMP9 (47{\%}) and NPT+Gem+αMMP9 (94{\%}). Six-week maintenance therapy revealed that median animal survival was significantly increased after NPT+Gem (186{\%}) and further improved by the addition of αMMP9 antibody (218{\%}). Qualitative assessment of mice exhibited that αMMP9 therapy led to a reduction in jaundice, bloody ascites and metastatic burden. Anti-MMP9 antibody increased the levels of tumour-associated IL-28 (1.5-fold) and decreased stromal markers (collagen I, αSMA) and the EMT marker vimentin. Subcutaneous tumours revealed low but detectable levels of MMP9 in all therapy groups but no difference in MMP9 expression. Anti-MMP9 antibody monotherapy resulted in more gene expression changes in the mouse stroma compared to the human tumour compartment. These findings suggest that anti-MMP9 antibody can exert specific stroma-directed effects that could be exploited in combination with currently used cytotoxics to improve clinical PDAC therapy.",
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AB - Matrix metalloproteinase 9 (MMP9) is involved in the proteolysis of extracellular proteins and plays a critical role in pancreatic ductal adenocarcinoma (PDAC) progression, invasion and metastasis. The therapeutic potential of an anti-MMP9 antibody (αMMP9) was evaluated in combination with nab-paclitaxel (NPT)-based standard cytotoxic therapy in pre-clinical models of PDAC. Tumour progression and survival studies were performed in NOD/SCID mice. The mechanistic evaluation involved RNA-Seq, Luminex, IHC and Immunoblot analyses of tumour samples. Median animal survival compared to controls was significantly increased after 2-week therapy with NPT (59%), Gem (29%) and NPT+Gem (76%). Addition of αMMP9 antibody exhibited further extension in survival: NPT+αMMP9 (76%), Gem+αMMP9 (47%) and NPT+Gem+αMMP9 (94%). Six-week maintenance therapy revealed that median animal survival was significantly increased after NPT+Gem (186%) and further improved by the addition of αMMP9 antibody (218%). Qualitative assessment of mice exhibited that αMMP9 therapy led to a reduction in jaundice, bloody ascites and metastatic burden. Anti-MMP9 antibody increased the levels of tumour-associated IL-28 (1.5-fold) and decreased stromal markers (collagen I, αSMA) and the EMT marker vimentin. Subcutaneous tumours revealed low but detectable levels of MMP9 in all therapy groups but no difference in MMP9 expression. Anti-MMP9 antibody monotherapy resulted in more gene expression changes in the mouse stroma compared to the human tumour compartment. These findings suggest that anti-MMP9 antibody can exert specific stroma-directed effects that could be exploited in combination with currently used cytotoxics to improve clinical PDAC therapy.

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