B358 SF1126, A Novel PI3K Inhibitor Results in Downstream Inhibition of the PI3K Axis and Displays Sequen

Malignant plasma cells alter the bone microenvironment resulting in osteolytic lesions, a typical feature of multiple myeloma (MM). Using a cytokine array in MM patients with bone disease, we identified activin A, a member of the TGFsuperfamily as a critical pathway with bone catabolic effects. By ELISA assay, we studied activin A expression in bone marrow (BM) plasma of MM patients and ex vivo–derived BM cell supernatant. In vitro and in vivo effects of activin A inhibition were investigated using a soluble receptor, RAP-011 (Acceleron Pharma Inc., Cambridge). The in vivo studies were performed using the SCID-hu mouse model, consisting of INA6 cells engrafted in a human fetal bone chip. MM patients with osteolytic lesions had a 4-fold increase in activin A expression compared with MM patients with < 1 lesion and non-MM patients (average 123.6 136 vs. 26.4 21.4 vs. 30.6 25.1 pg/mL, respectively, P < .05). The main source of activin were BM stromal cells (BMSCs), followed by osteoclasts, and osteoblasts (average levels in 72h supernatant were 1884, 1300, 299 pg/mL, respectively). In contrast, MM cells did not secrete activin but stimulated its secretion in co-culture by BMSC (1.3to 2-fold increase). Activin A inhibited OB differentiation (30% reduction of ALP activity; P < .05) and function (80% inhibition of mineralization; P < .01). RAP-011 enhanced OB differentiation and activity (5-fold increase in calcium deposition at day 21; P < .05) and reversed the inhibitory effects of MM cell lines (INA6 and MOLP5) as well as patient-derived MM cells on OB. Enhanced OB differentiation by RAP-011 resulted in inhibition of MM cell proliferation compared to BMSCs and mature OB. In vivo, treatment with RAP-011 decreased the number of osteolytic lesions and improved bone density assessed by CT imaging. An inhibition of tumor growth measured by soluble human IL-6 receptor levels (P < .02) was also noted. These data suggest that activin A is involved in development of MM bone disease and can be effectively inhibited by a soluble receptor, RAP-011. Our results support the use of the humanized clinical-grade form ACE-011 as a novel therapeutic approach for the treatment of MM.