Inhibiting activin-A signaling stimulates bone formation and prevents cancer-induced bone destruction in vivo

Abstract

Cancers that grow in bone, such as myeloma and breast cancer metastases, cause devastating osteolytic bone destruction. These cancers hijack bone remodeling by stimulating osteoclastic bone resorption and suppressing bone formation. Currently, treatment is targeted primarily at blocking bone resorption, but this approach has achieved only limited success. Stimulating osteoblastic bone formation to promote repair is a novel alternative approach. We show that a soluble activin receptor type IIA fusion protein (ActRIIA.muFc) stimulates osteoblastogenesis ( p < .01), promotes bone formation ( p < .01) and increases bone mass in vivo ( p < .001). We show that the development of osteolytic bone lesions in mice bearing murine myeloma cells is caused by both increased resorption ( p < .05) and suppression of bone formation ( p < .01). ActRIIA.muFc treatment stimulates osteoblastogenesis ( p < .01), prevents myeloma-induced suppression of bone formation ( p < .05), blocks the development of osteolytic bone lesions ( p < .05), and increases survival ( p < .05). We also show, in a murine model of breast cancer bone metastasis, that ActRIIA.muFc again prevents bone destruction ( p < .001) and inhibits bone metastases ( p < .05). These findings show that stimulating osteoblastic bone formation with ActRIIA.muFc blocks the formation of osteolytic bone lesions and bone metastases in models of myeloma and breast cancer and paves the way for new approaches to treating this debilitating aspect of cancer. ß

Bone Anabolic Agents for the Treatment of Multiple Myeloma

“…Interestingly, neither of these models showed a significant difference in OC number. The anabolic effects of RAP-011 have also been confirmed in mouse models of breast cancer associated-bone disease and osteoporosis [52,93]. A phase I dose-escalation trial in healthy postmenopausal women showed dose-dependent increase in serum levels of bALP, persisting up to 120 days after a single intravenous injection of 3-mg/kg.…”

“…Compared with vehicle, RAP-011 increased OB number, bone surface occupied by OB and mineralization. Again RAP-011 yielded a 41% reduction in serum paraprotein levels and a 37% reduction in the tumor burden of bone [52]. Interestingly, neither of these models showed a significant difference in OC number.…”

“…Other roles of activin A include regulation of craniofacial development, gonadal function via modulation of FSH secretion and erythropoiesis [50,51]. Promising preclinical data using inhibitors of activin A signaling have been obtained in breast cancer and MM mouse models [47,52]. Known to stimulate bone resorption and tumor growth in breast cancer, TGFβ also inhibits differentiation of mesenchymal stem cells and preosteoblastic cell lines into OBs, at least partially via downregulation of RUNX2 and DLX5 expression [46,53].…”

“…It sequesters activin A from binding to its membrane bound receptor, thus promoting osteogenesis. The murine counterpart of sotatercept, referred to as RAP-011, has been extensively preclinically evaluated in mouse models of cancer-and osteoporosis-related bone loss [47,52,93]. In vitro inhibition of activin A increases OB differentiation overcoming the inhibitory effect of MM cells.…”

The role of bone morphogenetic proteins in myeloma cell survival

“…[80] Activin A levels were increased in bone marrow plasma of myeloma patients with osteolytic disease and has been proposed to play an important role in myeloma bone disease, at least in part by inhibiting phosphorylation of SMAD1/5/8 during osteoblastogenesis. [81,82] Lenalidomide treatment has been shown to cause activin A secretion by myeloma BMSC, providing a rationale for a combination treatment of lenalidomide with activin A inhibition. [83] TGF-β is abundant in the bone marrow of myeloma patients, and represses bone formation in osteolytic lesions.…”