Targeting MMP14 to reduce metastases and potentiate the efficacy of radiation therapy in aggressive triple-negative breast cancer

• Applicant: Dr. Vasileios Askoxylakis
• Subject Area: Nuclear Medicine, Radiotherapy, Radiobiology
• Term: from 2013 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 235085719

Breast cancer is the most common cancer in women in developed countries, representing a major health care problem. A particularly aggressive subtype is the triple-negative breast cancer (TNBC). Triple negative breast cancer is found to be an independent predictor of distant metastasis and cause-specific survival and has an adverse prognosis. This fact reveals the necessity for the development of novel targeted therapeutic strategies. Matrix modifying proteins, called matrix metalloproteinases (MMP) possess key roles in cancer progression and metastasis and represent attractive structures for molecular targeting approaches. Among MMPs, matrix metalloproteinase 14 (MMP14) is upregulated in triple-negative breast cancer and is essential for the degradation of vascular basement membranes, promoting cancer cell intravasation and metastasis. Recent studies have demonstrated that knocking down MMP14 expression impairs the invasive potential of breast cancer cells and reduces their metastatic potential. Therefore, major aims of this project are to i) investigate the effects of specific molecular inhibition of MMP14 on tumor growth, metastatic potential and radiosensitivity of triple-negative breast cancer and ii) characterize the biological mechanisms involved in this process. Using established molecular biology methods and advanced techniques, such as intravital microscopy, as well as various animal models, the project will focus on two main aspects: The first aspect is the investigation of the potential of antibody-based, specific MMP14 inhibition on improving tumor response to radiation therapy by normalizing the tumor vasculature. Previous studies demonstrated that antiangiogenic agents increase oxygen concentrations in the tumor tissue, via their ability to transiently normalize the tumor vasculature. Since MMP14 is involved in tumor angiogenesis this project will investigate the hypothesis that MMP14 inhibition might also promote tumor vessel normalization, resulting in improved tumor oxygenation and enhanced radiosensitivity. The second aspect will focus on the characterization of interactions between antibody-based MMP14 inhibition and nitric oxide (NO) on the regulation of angiogenesis and tumor growth. Previous studies have revealed that the induction of a NO gradient around the tumor vessels can lead to vascular normalization, whereas a functional interplay between NO and MMP14 during endothelial cell migration has been demonstrated. Therefore, a major question that needs to be answered is the role of nitric oxide synthases (NOS) and the importance of NOS-generated nitric oxide in governing tumor response to MMP14 inhibition. If successful, the results of the preclinical work will form the basis for clinical trials, evaluating the effectiveness of targeted MMP14 inhibition and radiotherapy in the treatment of aggressive triple-negative breast cancer.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Rakesh K. Jain, Ph.D.