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

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.

• Authors: Niranjan Awasthi, Amanda J Mikels-Vigdal, Erin Stefanutti, Margaret A Schwarz, Sheena Monahan, Victoria Smith, Roderich E Schwarz
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 23 Issue 6 Pg. 3878-3887 (06 2019) ISSN: 1582-4934 [Electronic] England
• PMID: 30941918 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Chemical References

• 130-nm albumin-bound paclitaxel
• Acta2 protein, mouse
• Actins
• Albumins
• Antibodies, Monoclonal
• Cytokines
• Vimentin
• interferon-lambda protein, mouse
• Collagen
• MMP9 protein, human
• Matrix Metalloproteinase 9
• Paclitaxel

Topics

• Actins (metabolism)
• Albumins (therapeutic use)
• Animals
• Antibodies, Monoclonal (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Carcinoma, Pancreatic Ductal (drug therapy, metabolism)
• Cell Line, Tumor
• Collagen (metabolism)
• Cytokines (metabolism)
• Female
• Humans
• Matrix Metalloproteinase 9 (genetics, immunology, metabolism)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Paclitaxel (therapeutic use)
• Pancreatic Neoplasms (drug therapy, metabolism)
• RNA-Seq
• Tumor Microenvironment (drug effects, genetics)
• Vimentin (metabolism)
• Xenograft Model Antitumor Assays