Abstract 2134: Bone-targeted MMP inhibitors for the treatment of multiple myeloma.

Abstract

Abstract Multiple Myeloma (MM) is a plasma cell malignancy that is hallmarked by areas of extensive bone destruction. Our group, and others have recently shown that individual host or tumor derived MMP-2 and MMP-9 play an important role in the progression of many cancers in the bone microenvironment, including MM. These data support the design of selective inhibitors of individual MMPs for the treatment of multiple myeloma. Previous clinical trials with broad-spectrum matrix metalloproteinase (MMP) inhibitors failed, arguably because the precise roles of individual MMPs had not been fully appreciated. Therefore, in the current study, we have developed novel bone seeking MMP inhibitors (BMMPIs) that are highly selective to MMP-2 and structurally are based on the bone targeting bisphosphonate, Tiludronate. In vitro, BMMPIs showed greater enzyme inhibition, and specificity for MMP-2 than previously synthesized bisphosphonates (e.g. Zoledronate, Etidronate and Tiludronate) with Ki values in the nanomolar range. Further treatment of the 5TGM1 mouse MM cell line with low micromolar concentrations of the BMMPI inhibitors significantly reduced cell viability through inhibition of cell growth (p<0.05). In vivo, 5TGMI tumor-bearing mice receiving BMMP inhibitors three times a week, showed significant increase in overall survival compared to vehicle and tiludronate treated mice over 80 days (p<0.05). This was associated with a reduction in tumor burden and protection from tumor-associated bone loss compared to vehicle treated mice as measured by x-ray and histomorphometry. These data suggest that given the roles for MMPs in tumor progression in bone, that our novel BMMPIs may be effective in the treatment of MM. We predict that MMP-2 specific BMMPIs may be more effective than current clinically used bisphosphonates for the treatment of MM, and may eliminate undesirable side effects of broad-spectrum MMP inhibitors due to their high specificity and bone seeking nature. We are currently continuing to characterize these BMMPI both as single agents, and in combination with existing MM treatments (eg. Bortezomib) for the treatment and eradication of MM. Citation Format: Gemma Shay, Marilena Tauro, Antonio Laghezza, Paolo Tortorella, Lori A. Hazlehurst, Conor C. Lynch. Bone-targeted MMP inhibitors for the treatment of multiple myeloma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2134. doi:10.1158/1538-7445.AM2013-2134