Pharmacologic inhibition of CSF-1R suppresses intrinsic tumor cell growth in osteosarcoma with CSF-1R overexpression.

Background: Osteosarcoma is the most common primary malignant bone tumor affecting children and young adults. Metastatic osteosarcoma has poor prognosis and represents a significant unmet medical need in clinical settings. The CSF-1/CSF-1R signaling pathway is essential for the physiological functions of myeloid lineage cells, including osteoclasts and monocytes/macrophages. The purpose of this study is to investigate the role of CSF-1R in osteosarcoma pathogenesis and the therapeutical potentiality of CSF-1R inhibitor for osteosarcoma patients.

Methods: CSF-1, CSF-1R, and IL-34 expression across cancer types were evaluated using public database. Immunohistochemistry (IHC) was utilized to analyze human tissue microarray samples of osteosarcoma. We then investigated the anti-tumor effect and the mechanisms of action of pharmacologic inhibition of CSF-1R activity by pimicotinib (ABSK021), a highly potent and selective small molecule inhibitor of CSF-1R, in osteosarcoma models both in vitro and in vivo.

Results: IHC analysis of human tissue microarray samples revealed a high prevalence of CSF-1R overexpression in osteosarcoma patient samples. ABSK021 effectively inhibited CSF-1R signaling and the proliferation of osteosarcoma cells with high expression of CSF-1R, by inducing cell cycle arrest and apoptosis. In contrast, it had a marginal effect on osteosarcoma cell lines with low CSF-1R expression. In animal studies, ABSK021 demonstrated strong anti-tumor activity in both a syngeneic mouse osteosarcoma model and osteosarcoma patient sample-derived xenograft (PDX) models with CSF-1R overexpression. The analysis of endpoint tumor samples revealed downregulation of CSF-1R signaling and proliferative marker Ki67, along with the increase of apoptotic marker cleaved caspase-3, confirming the on-target effects of ABSK021 in vivo. Furthermore, combining ABSK021 with standard-of-care chemotherapy showed enhanced anti-tumor activity both in vitro and in vivo.

Conclusions: These findings conclusively demonstrated that pharmacological inhibition of CSF-1R activity by ABSK021 resulted in significant anti-tumor effects in preclinical osteosarcoma models with CSF-1R overexpression. The high prevalence of CSF-1R expression observed in osteosarcoma patient samples highlights the potential clinical use of ABSK021, either as a monotherapy or in combination with chemotherapy, as a promising therapeutic strategy for osteosarcoma patients with CSF-1R as a potential predictive biomarker.