Abstract 693: Effects of a bone-anabolic agent on metastatic bone cancer growth

Abstract

Abstract Introduction: Cancer cells colonized to bone pathologically alter the bone niche to support the cancers' growth and survival. Multiple myeloma (MM) and metastatic solid tumors, particularly breast cancer (BC), activate osteoclasts and suppress osteoblasts leading to many complications and an increased mortality risk. Current strategies primarily target osteoclasts. Known osteoclast activating factor PTHrP is expressed by MM cells and BC cells and may contribute to progression. We hypothesized that alteration of PTH receptor signaling should overcome cancers' inhibition of bone formation and decrease cancer growth in bone. BDDP, a novel PTH analog, is being developed for osteoporosis treatment. We determined the ability of BDDP to reverse osteoblast suppression and slow tumor growth in bone with MM and BC models. Methods: In vitro effects of BDDP on bone genes and bone mineralization were tested in a co-culture assay of osteoblastic MC3T3-E1 cells ± human MM.1s cells. After 3 days in proliferative media, they were cultured in differentiation media. At Day 7, the expression of genes with known roles in osteoblast differentiation were assayed by RT-PCR. At Day 25, nodular calcification was stained and measured by a colorimetric assay. In vivo effects of BDDP were evaluated in an intratibial transplant model. MDA-MB-231 BC cells expressing secreted luciferase were injected into the ipsilateral tibiae of Balb/cnu/nu mice. Mice received either BDDP (40μg/kg/d) or vehicle via osmotic pump for 30 days. After euthanasia, mice were subjected to Faxitron digital X-rays to detect osteolytic lesions and DEXA scans to assess bone mineral content (BMC) and bone mineral density (BMD). Tumor-injected and non-injected tibiae were subjected to micro-QCT for 3D tibiae imaging. Results: MM.1s-treated MC3T3-E1 cells showed approximately a 5-fold reduction in osteoblast differentiation gene RUNX2 and a 3-fold reduction in BGLAP. This effect was attenuated by 100 nM BDDP by approximately 4-fold in both Runx2 and BGLAP. BDDP increased nodular calcification. Nodular calcification was suppressed in MM.1s-treated MC3T3-E1 cells. This effect was reversed by BDDP. BDDP did not directly affect MM.1s and MDA-MB-231 growths in culture but showed dramatic tumor suppression in a MDA-MB-231 intratibial transplant model. Tumor burden assayed by serial serum luciferase assay showed BDDP-treated group to be 95% lower than control, at 3 and 4 weeks post-transplant. Tumor-injected tibiae had lytic lesions in all control mice, while there were no obvious lesions in BDDP-treated mice. There were no significant changes in the trabecular bone of non-injected tibiae, whole body composition, BMC or BMD. Conclusion: BDDP reverses osteoblastic suppression by MM cells in vitro, as well as inhibiting tumor growth and preventing local bone destruction in the BC intratibial transplant model, thereby making BDDP a promising potential treatment strategy for metastatic bone cancers. Citation Format: Teja Vallapuri, Colin Crean, John Chirgwin, G. David Roodman, Attaya Suvannasankha. Effects of a bone-anabolic agent on metastatic bone cancer growth [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 693.