Targeting MMP14 to reduce metastases and potentiate the efficacy of radiation therapy in aggressive triple-negative breast cancer
Final Report Abstract
Triple negative breast cancer (TNBC) is a particular aggressive breast cancer subtype. It accounts for about 15-20% of all breast cancer cases and frequently strikes younger women. The fact that TNBC has an adverse prognosis, associated with an increased metastatic potential, reveals the necessity for the development of novel therapies. Matrix metalloproteinases (MMPs) are matrix modifying proteins with key roles in cancer progression and metastasis. Among them, MMP14 has been shown to be overexpressed in TNBC. Therefore, MMP14 may represent an attractive target for novel antineoplastic therapies. My research in this project aimed in determining, whether selective MMP14 inhibition can improve breast cancer response to radiation therapy and identify possible mechanisms that contribute to the effects of MMP14 inhibition in TNBC. To realize these aims I used established breast cancer cell lines, clinically relevant animal models, state-of-the-art molecular biology techniques and powerful, non-invasive, high resolution imaging technologies that provide unprecedented molecular, cellular, structural and functional insights. The results of this project show that highly selective MMP14 inhibition using the antibody DX- 2400 can increase vascular perfusion and reduce hypoxia in murine breast cancer models, and improve the efficacy of radiation therapy. Treatment with DX-2400 was associated with a decrease in active TGFβ - an immunosuppressive cytokine - in murine breast cancer tissue. Consistent with this, macrophages were shifted towards antitumor phenotype. Mechanistic analysis indicated the beneficial effects of MMP14 blockade in combination with radiation may be mediated by inducible nitric oxide synthase (iNOS). However, variability in the effects of MMP14 inhibition was noticed between breast cancer models with different endogenous MMP14 and iNOS expression. The findings of this project suggest MMP14 as a potential therapeutic target to modulate the tumor microenvironment. Furthermore, they suggest iNOS induction as potential biomarker. These findings may directly inform the design and help interpret the results of future studies on MMP14 targeted therapies aiming in improving the prognosis of triple-negative breast cancer.
Publications
- Blockade of MMP14 activity in murine breast carcinomas: implications for macrophages, vessels, and radiotherapy. J Natl Cancer Inst 2015;107(4)
Ager EI, Kozin SV, Kirkpatrick ND, Seano G, Kodack DP, Askoxylakis V, Huang Y, Goel S, Snuderl M, Muzikansky A, Finkelstein DM, Dransfield DT, Devy L, Boucher Y, Fukumura D, Jain RK
(See online at https://doi.org/10.1093/jnci/djv017)
