Abstract P6-17-02: Inhibition of osteolytic tumor growth by 5-FdU-alendronate, a bisphosphonate conjugate that maintains bone formation: Implications for treatment of osteolytic bone lesions

Abstract

Patients with breast cancer bone metastases suffer significant morbity from skeletal-related events but an effective agent that inhibits bone resorption while maintaining bone formation has not been identified. In this study we tested the therapeutic efficacy of a novel drug, 5-FdU-ale, a conjugate between the anti-metabolite 5-FdU and the bisphosphonate alendronate, in a mouse model of breast cancer bone metastases. Administration of 5-FdU-ale in vitro induces cell cycle arrest similar to treatment with unconjugated 5-FdU. In vivo, mice harboring bone lesions treated with 5-FdU-ale showed a reduction in tumor size not observed with administration of either Alendronate or 5-FdU. Since osteolysis mediated release of growth factors from bone contribute to tumor growth, we show 5-FdU-ale treatment significantly reduces bone resorption, although uniquely, the inhibition of osteoclast activity is not mediated through inhibition of prenylation of small GTPases. Furthermore, and in contrast to Alendronate, there is no concomitant decrease in bone formation activity, as determined by serum osteocaclin levels. This finding is supported by micro-CT analyses which reveal significantly higher bone volume and histologically, pockets of tumor cells are observed largely confined to regions of marrow space between endochondral and trabecular bone. Taken together, we conclude that 5-FdU-ale has potent anti-tumor efficacy in osteolytic bone lesions mediated uniquely through bone formation activity of osteoblasts and inhibition of bone resorption. The study identifies the important role of osteoblast in not only preventing the osteolytic metastatic phenotype but as a means of harnessing the therapeutic potential of bone formation to treat osteolytic lesions. Citation Format: Christian Schem, Rob J Tower, Philipp Kneissl, Anna C Rambow, Graeme M Campbell, Thorsten Heilmann, Anna Trauzold, Walter Jonat, Claus C Glüer, Sarah Schott, Sanjay Tiwari. Inhibition of osteolytic tumor growth by 5-FdU-alendronate, a bisphosphonate conjugate that maintains bone formation: Implications for treatment of osteolytic bone lesions [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-17-02.