Abstract 4858: A novel strategy for the selective and tissue specific inhibition of MMPs in active breast cancer to bone metastases
Authors: Tauro Marilena , Laghezza Antonio , Tortorella Paolo , Lynch Conor C. 
Published: May 2015

Bone metastasis is a common event during breast cancer progression: The delicate balance between bone matrix synthesizing osteoblasts and bone resorbing osteoclasts activities is typically subverted by the presence of tumor cells at the bone site. The resulting incurable lesions cause extensive osteolysis and severely impact the patient's quality of life. Understanding how active breast-to-bone metastases manipulate the bone microenvironment is critical for the development of new therapies to treat the disease. We have recently shown in preclinical animal models of breast to bone metastases that MMP-2 proteolytic activity is critical for the growth of the tumor and the associated osteolysis. We therefore hypothesized that the selective inhibition of MMP-2 at the tumor site would be a potent means through which to prevent the progression of the malignancy. Given that previous broad-spectrum MMP inhibitor (MMPI) trials were unsuccessful mainly because of consistent side effects, we took a novel chemical approach to generate a selective MMPI that would preferentially target the skeleton. To this end, we utilized a bisphosphonate backbone (tiludronate) to synthesize an MMPI (BMMPI) with high specificity for MMP-2 (IC50 0.14± 0.04μM). To test the efficacy of the BMMPI in vivo, we inoculated 6-week old immunocompromized female mice with a luciferase expressing osteolytic breast cancer cell line, PyMT-Luc (105 cells). Following tumor injection, mice (n=6/group) received saline, tiludronate (25mg/kg, to control for bisphosphonate effects) or BMMPI (25mg/kg) sub-cutaneously, twice weekly. Tumor growth was measured by quantitating luminescence over time. Our results show that application of the BMMPI significantly reduced the breast cancer growth over a two-week period (p&lt;0.05). Furthermore, using Faxitron analysis to determine the extent of tumor induced bone destruction, we observed significantly less osteolysis in the tibia images of BMMPI treated mice compared to the control group. Our initial studies also suggest that BMMPIs perform better than clinically used bisphosphonates such as tiludronate. We are currently following up our in vivo/ex vivo analyses with histomorphometrical and histology approaches. In conclusion, our data thus far demonstrate that an MMP-2 specific BMMPI may be an effective means to prevent the progression of breast to bone metastases while at the same time eliminating some of the noted off-target effects of broad-spectrum MMP inhibitors. Since bisphosphonates are well tolerated in the clinical setting, we predict that BMMPIs could be rapidly translated to the patient.

Citation Format: Marilena Tauro, Antonio Laghezza, Paolo Tortorella, Conor C. Lynch. A novel strategy for the selective and tissue specific inhibition of MMPs in active breast cancer to bone metastases. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4858. doi:10.1158/1538-7445.AM2014-4858