Abstract 541: The oral proteasome inhibitor ONX 0912 has bone anabolic effects in addition to anti-myeloma effects

Abstract

Abstract Multiple Myeloma (MM) is a cancer of antibody producing plasma cells in which tumors largely reside in and destroy the bone microenvironment. Drugs that inhibit proteasomal degradation of intracellular proteins such as those crucial for cell growth, have demonstrated significant efficacy in the treatment of MM. ONX 0912, is a next generation proteasome inhibitor that acts irreversibly and has the significant advantage of oral delivery. Pharmacokinetic data suggest that the in vivo serum half life of ONX 0912 is approximately 4 hours. We found that a physiologic 4 hour pulse treatment with low nanomolar doses of ONX 0912 effectively decreased the viability of human MM cell lines through the inhibition of proliferation and induction of apoptosis with similar efficacy as continuous drug administration in vitro. Because MM induces significant bone loss through the tumoral production of factors involved in the recruitment of bone resorping osteoclasts (OC) and suppression of bone forming osteoblasts (OB), we also evaluated the effects of ONX 0912 on bone cell viability and function. Bortezomib, an intravenous proteasome inhibitor in clinical use with a serum half-life of one hour, has been reported to suppress OC viability and enhance OB function. We found that culturing of primary murine macrophages, preosteoclasts, and OC under continuous incubation with bortezomib and ONX 0912 decreased cell viability, although at doses greater than 100-fold higher than those affecting MM cells. However, when primary macrophages and OC were incubated with a physiologic 1 hour pulse of bortezomib or 4 hour pulse of ONX0912, these cells were resistant to killing with in vitro osteoclastogenesis being modestly inhibited. In contrast, physiologic 4 hour pulse exposure of ONX 0912 to primary OB cultures, resulted in enhanced in vitro differentiation and mineralization. Likewise, oral administration of ONX 0912 to non-tumor bearing C57BL/6 mice significantly increased trabecular bone volume and bone mineral density. We then evaluated the effect of ONX 0912 on MM tumor burden and tumor associated bone loss in vivo. Oral administration of ONX 0912 significantly reduced the growth of human RPMI8226 MM cells in long bones of NOD-SCID-IL-2Rγc-/- mice and protected mice from bone loss compared to vehicle treated mice. These data suggest that, in addition to its anti-tumor effects, ONX 0912 may also shift the bone microenvironment during MM from a catabolic state to an anabolic state, reducing osteolysis, promoting bone formation and decreasing skeletal complications of MM. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 541. doi:10.1158/1538-7445.AM2011-541