BACKGROUND: Matrix metalloproteinase 9 (MMP9) is involved in the proteolysis of extracellular proteins and is reported to play a key role in development, invasion and metastasis of many cancers including pancreatic ductal adenocarcinoma (PDAC). Andecaliximab is a potent and highly selective monoclonal antibody inhibitor of MMP9 that has shown antitumor activity in combination with chemotherapy in gastric cancer. The therapeutic potential of targeted MMP9 inhibition in combination with cytotoxic therapy in preclinical models of PDAC was evaluated through the use of an αMMP9 antibody.
METHODS: Animal survival and qualitative analysis were performed in the peritoneal dissemination model in mice using 7.5x105 AsPC-1 cells. Tumor growth study was performed in subcutaneous xenografts in mice using 7.5x105 AsPC-1 cells. The mechanistic evaluation involved RNASeq, Luminex, IHC and Immunoblot analysis in tumor samples.
RESULTS: Median animal survival compared to controls (17 days) was increased after 2-week therapy with NPT (27 days, a 59% increase), Gem (22 days, +29%) and NPT+Gem (30 days, +76%). Addition of αMMP9 antibody increased survival as follows: NPT+MMP9 (30 days, +76%), Gem+MMP9 (25 days, +47%) and NPT+Gem+MMP9 (33 days, +94%). Evaluation of efficacy of maintenance therapy (6-weeks) revealed that median animal survival (controls: 22 days) was increased after NPT+Gem therapy (63 days, +186%) and further improved by addition of αMMP9 antibody (70 days, +218%). Qualitative assessment of mice after 2-week therapy revealed that αMMP9 therapy led to reduction in jaundice, bloody ascites and metastatic burden, both alone and in combination with NPT+Gem. Tumor lysates demonstrated changes in several proteins in chemotherapy groups including IP-10, MDC, PAI-1, GM-CSF, MIP-1b and IL-12b. αMMP9 therapy increased IL-28 (1.5 fold, p = 0.016). IHC analysis revealed decreased tumor microvessel density based on endomucin staining in αMMP9 therapy groups (59.9%, p<0.0001). Immunoblot analysis showed decreased vimentin expression in αMMP9 therapy groups (42.5%, p =0.03). In tumor growth study, NPT+Gem significantly decreased tumor growth (72%, p=0.0005) compared to controls. αMMP9 therapy caused a non-significant decrease in tumor growth (17%, p=0.24). Tumor tissues revealed low, but detectable levels of MMP9 mRNA in all therapy groups but no difference in MMP9 expression. αMMP9 monotherapy resulted in more gene expression changes in the mouse stromal than the human tumor compartment compared to other treatments. However, NPT+Gem+MMP9 combination therapy resulted in greater numbers of changes in gene expression compared to the other treatments in the tumor compartment.
CONCLUSION: These findings suggest that MMP9 inhibition can augment the effects of standard cytotoxic therapy and support the potential of this combination therapeutic strategy for clinical PDAC therapy.
Citation Format: Niranjan Awasthi, Amanda Mikels-Vigdal, Erin Stefanutti, Margaret A. Schwarz, Sheena Monahan, Victoria Smith, Roderich E. Schwarz. Anti-MMP9 antibody in combination with standard cytotoxic therapy in preclinical models of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4822.