Objectives:

Bisphosphonates, known to have beneficial effects on bone and soft tissue metastases in breast cancer, are potent inhibitors of macrophages, but effects on the microenvironment are not fully understood. We investigated the biological effect of clodronate on macrophage and endothelial cell-driven angiogenesis in ovarian cancer.

Methods:

Using the FDA Adverse Event Reporting System (FAERS), we examined the effects of bisphosphonate use on overall cancer mortality. We examined the in vitro (endothelial cell migration, capillary formation and cytokine secretion) and in vivo (orthotopic mouse models) effects of clodronate on angiogenesis, macrophage infiltration, and tumor growth.

Results:

Using (FAERS) data, out of ∼17,000 patients with a cancer diagnosis co-medicated with a bisphosphonate, overall reported death rate was 36% lower (17.6% vs 27.7%, p<0.0001) than those not receiving bisphosphonates, independent of anti-tumor therapy. In vitro, treatment with clodronate resulted in decreased endothelial cell secretion of IL-6 (p < 0.001), IL-8 (p < 0.001), and a 2.5-fold reduction in cell migration compared to controls (p < 0.001), with only partial recovery after VEGF stimulation. Clodronate reduced capillary formation by 1.5-fold compared to controls. In the ID8-VEGF model, clodronate-treated mice had a 5-fold decrease in tumor weight (0.05g vs. 0.3g, p < 0.001) compared to controls. In the SKOV3ip1 model, clodronate treatment resulted in a 3-fold decrease in tumor weight (0.35g vs. 0.96g, p = 0.003) and tumor nodules (5.2 vs. 16, p=0.005) compared to controls. Immunohistochemical staining of clondronate-treated tumor sections showed a 2-fold and 1.5-fold (ID8-VEGF and SKOV3ip1, respectively) reduction in macrophage density (p=0.001 and p < 0.001, respectively) compared to controls. Clodronate-treated tumor sections showed a 3-fold decrease in capillary density (p < 0.001) compared to controls.

Conclusions:

Bisphosphonates modulate tumor angiogenesis through effects on macrophages and endothelial cells and are associated with overall decreased mortality in cancer patients, independent of chemotherapeutic agents. Bisphosphonates represent an unexplored, but attractive clinical strategy in ovarian cancer, with potential for synergistic combination with other anti-angiogenic agents.

Citation Format: Heather J. Dalton, Nicole M. Reusser, Alexander Zien, David Jackson, Rebecca Previs, Rajesha Rupaimoole, Behrouz Zand, Gabriel Lopez-Berestein, Robert L. Coleman, Anil K. Sood. Bisphosphonates: New strategies for targeting angiogenesis in ovarian cancer. [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 2983. doi:10.1158/1538-7445.AM2014-2983