Efficacy of an orally active small-molecule inhibitor of RANKL in bone metastasis

Abstract

Bone is one of the preferred sites for the metastasis of malignant tumours, such as breast cancer, lung cancer and malignant melanoma. Tumour cells colonizing bone have the capacity to induce the expression of receptor activator of nuclear factor-κB ligand (RANKL), which promotes osteoclast differentiation and activation. Tumour-induced osteoclastic bone resorption leads to a vicious cycle between tumours and bone cells that fuels osteolytic tumour growth, causing bone pain and hypercalcaemia. Furthermore, RANKL contributes to bone metastasis by acting as a chemoattractant to bone for tumour cells that express its receptor, RANK. Thus inhibition of the RANKL–RANK pathway is a promising treatment for bone metastasis, and a human monoclonal anti-RANKL antibody, denosumab, has been used in the clinic. However, orally available drugs targeting RANKL must be developed to increase the therapeutic benefits to patients. Here we report the efficacy of the small-molecule RANKL inhibitor AS2676293 in treating bone metastasis using mouse models. Oral administration of AS2676293 markedly inhibited bone metastasis of human breast cancer cells MDA-MB-231-5a-D-Luc2 as well as tumour-induced osteolysis. AS2676293 suppressed RANKL-mediated tumour migration in the transwell assay and inhibited bone metastasis of the murine cell line B16F10, which is known not to trigger osteoclast activation. Based on the results from this study, RANKL inhibition with a small-molecule compound constitutes a promising therapeutic strategy for treating bone metastasis by inhibiting both osteoclastic bone resorption and tumour migration to bone.

RANKL biology: bone metabolism, the immune system, and beyond

“…Therefore, inhibition of the RANKL/RANK pathway can break the vicious cycle and suppress bone metastasis [112]. Recently, it was reported that oral administration of AS2676293, a small-molecule inhibitor of RANKL, reduced bone metastasis of breast cancer cells and malignant melanoma by inhibiting not only bone resorption but also RANKL-induced tumor migration in a murine model [113].…”

Bone Tumors: Types and Treatments

“…4. Growth factors such as transforming growth factor (TGF)-β, insulin-like growth factors (IGFs), bone morphogenetic proteins (BMPs), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) released from degraded bone matrices also promote tumor cell proliferation by production of PTHrP that interacts with parathyroid hormone (PTH)/PTHrP receptors in the bone and kidney to cause hypercalcemia, osteoclast-mediated bone resorption, increased nephrogenous cyclic AMP, and phosphate excretion [4][5][6]25]. PTH is known to regulate osteosarcoma cells, by inducing transcription of c-Fos that in turn targets calcium/cAMP-response element (CRE) through activation of protein kinase A (PKA) [26].…”

“…After tumor cells colonize the bone, they induce the expression of receptor activator of nuclear factor-κB ligand (RANKL) via production of PTHrP, prostaglandin E2 (PGE2), interleukin 6 (IL-6), IL-1β, TNF, and epidermal growth factor (EGF), which promote osteoclast differentiation and activation. RANKL induces osteoclastic bone resorption resulting in growth of osteolytic tumor that causes hypercalcemia, and it also acts as a chemoattractant to the bone for tumor cells [6]. In relation to this, hypoxia-inducible factor (HIF)-1α has been reported to act as an upstream master switch to many of the osteolytic factors such as IL-11 and IL-8 and angiogenic factors such as PDGF and vascular endothelial growth factor (VEGF) [4,31].…”

“…Osteolytic bone metastases are most often caused by breast cancer and multiple myeloma [6,33], whereas osteoblastic metastases are mostly observed in bone metastasis of prostate cancer, which is due to osteoblast stimulation by cancer cells [6,34]. Factors that are locally produced by cancer cells, such as bone BMP, IGF, FGF, TGF-β, and endothelin-1, also promote osteoblast proliferation and bone formation [6].…”

“…Tumor cells therefore migrate to the heavily vascularized areas of the skeleton, particularly the red bone marrow of the axial skeleton and the proximal ends of the long bones, the ribs, and the vertebral column [5]. Chemotactic factors such as CXCL10 (CXC motif ligand [CXCL]), CXCL12, and osteopontin have been reported to play a major role in tumor migration [6].…”