The combination of different therapeutic approaches, such as simultaneous targeting of tumor cells and stroma, may be a superior strategy to enhance anti-tumor responses in metastatic breast cancer (BC). Recently, the pro-tumorigenic activity of adipose tissue was further examined and suggested MMP9 promotes BC invasion, angiogenesis, and lung metastasis in mice (Reggiani et al., Cancer Res 2017). In the present work, MMP9 inhibition was combined with distinct therapeutic agents.
A monoclonal antibody that inhibits mouse MMP9 was administered to tumor-bearing (4T1) immune-competent BALB/c mice, alone or in combination with low-dose chemotherapy (vinorelbine, V or cyclophosphamide, CTX) or checkpoint inhibitors (anti-PD1 or anti-PDL1 monoclonal antibodies). MMP9 inhibition was also evaluated in diet-induced obese BC mice (Balb/c or FVB background).
The anti-tumor response of different combination treatments was assessed by tumor growth measurement, lung metastasis assessment, tumor angiogenesis evaluation through immunofluorescence, and immune system modulation by flow-cytometry.
The combination of V and MMP9 inhibition was superior to either agent alone. Tumor growth was reduced in mice administered with combined V and MMP9 inhibition compared to single treatment or control mice, administered with isotype control and saline (41% V+anti-MMP9 vs control, p=0.001). Lung metastases were significantly impaired (37% V+anti-MMP9 vs control, p=0.009). MMP9 inhibition exhibited the greatest reduction in intratumor angiogenesis among therapeutic agents tested (59% vs control, p=0.004). The combination of MMP9 inhibition with V compared to control, reduced B (1%, p=0.008), T cells (2.5%, p=0.01), and macrophages (35%, p=0.05) in the tumor.
Inhibiting MMP9 in diet-induced obese BALB/c mice was more effective in reducing tumor growth and metastatic progression, when compared to normal-weight mice (BC volume: 46%, p=0.01; lung metastasis: 53%, p=0.01). These data suggest that the increase of MMP9 release, observed in adipose progenitors when exposed to BC cells (Reggiani et al., Cancer Res 2017), was a mediator of the obesity-dependent pro-tumorigenic activity. Of note, when MMP9 inhibition was initiated in early phases of tumor growth in ErbB2+ BC FVB mice, the reduction of local tumor growth was more pronounced (started at 15 days vs 45 days: 18%, p=0.01; 15 days vs isotype control: 11%, p=0.01; 45 days vs isotype control: 64%, p=0.3 ns).
MMP9 inhibition is efficacious in mouse models of BC with concomitant obesity. In human BC patients, response to chemotherapy is reportedly lower, and the risk of relapse is higher in obese sub-population (Ewertz et al., JCO 2011). The additive effects of MMP9 inhibition with V may warrant further studies to characterize underlying molecular mechanisms in BC patients with high body mass index (BMI).
Citation Format: Francesca Reggiani, Loredana Vecchi, Valentina Labanca, Patrizia Mancuso, Amanda Mikels-Vigdal, Francesco Bertolini. MMP9 inhibition in mouse models of breast cancer: Therapeutic synergy with vinorelbine-based chemotherapy [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 18.