4859

ATN-224, an orally available small molecule inhibitor of SOD1, inhibits multiple signaling pathways associated with myeloma progression and has antitumor activity in a murine model of refractory myeloma growth.

Tuesday, Apr 04, 2006, 4:10 PM - 4:25 PM

Room 151, Washington Convention Center

Richard A. Campbell, Melinda S. Gordon, Oscar Betancourt, Jose Juarez, Fernando Donate, Andrew Mazar, James R. Berenson. Institute for Myeloma & Bone Cancer Research, W. Hollywood, CA, Attenuon, LLC, San Diego, CA

ATN-224 is an orally available small molecule inhibitor of the cytoplasmic enzyme superoxide dismutase 1 (SOD1) that is currently entering Phase II clinical trials in multiple cancer indications. ATN-224 has pleiotropic effects on both endothelial cells and tumor cells, leading to the inhibition of angiogenesis and the induction of tumor cell apoptosis in vitro and in vivo. ATN-224 interferes with a number of signaling pathways in parallel, including those mediated by VEGF, FGF-2 and IGF-1. These pathways have been implicated in myeloma progression, leading us to evaluate the effects of ATN-224 on myeloma cells in vitro as well as in murine models of myeloma progression in vivo. ATN-224 inhibited IGF-1 mediated activation of ERK1/2 in MM.1S cells and induced apoptosis in several myeloma cell lines including MM.1S, MM.1R (a dexamethasone resistant subclone of MM.1S) and RPMI-8226 in a dose and time-dependent manner. ATN-224 was also evaluated in SCID-hu models of myeloma. LAGκ-1B tumors, originally isolated from a patient refractory to lenalidomide, melphalan and bortezomib, were transplanted intramuscularly into SCID mice. Fourteen days post-implantation, mice were randomized based on human IgG levels and treated with ATN-224 at 5 mg/kg, 15 mg/kg, and 50 mg/kg per day via oral gavage on a Monday-Friday schedule. Mice receiving the intermediate (15 mg/kg) and high doses of ATN-224 (50 mg/kg) showed marked inhibition of tumor growth and reduction of human IgG levels while there was little effect observed in the low dose treatment group (5 mg/kg). Additionally, when a late dose of bortezomib (0.125 mg/kg) was administered with low dose ATN-224 (5 mg/kg), the combination had significantly better antitumor activity than ATN-224 or bortezomib alone, indicating that ATN-224 could re-sensitize tumors that were previously resistant to bortezomib. ATN-224 was also found to inhibit the expression of a novel myeloma growth and pro-angiogenic factor produced by myeloma cells, pleiotrophin, in a dose-dependent fashion. We have previously demonstrated that pleiotrophin expression declines in myeloma patients that respond to anti-myeloma therapy, further substantiating the anti-myeloma activity of ATN-224. These data suggest that ATN-224 may be useful in treating patients with highly refractory myeloma and provide a rationale for the clinical development of ATN-224 in this indication.