Macrophages can be co-opted to contribute to neoplastic, neurologic, and inflammatory diseases.
Colony-stimulating factor 1 receptor (CSF1R)-dependent macrophages and other inflammatory cells can suppress the adaptive immune system in
cancer and contribute to angiogenesis,
tumor growth, and
metastasis. CSF1R-expressing osteoclasts mediate bone degradation in osteolytic
cancers and
cancers that metastasize to bone. In the
rare disease tenosynovial giant cell tumor (TGCT), aberrant CSF1 expression and production driven by a gene translocation leads to the recruitment and growth of
tumors formed by CSF1R-dependent inflammatory cells. Small molecules and
antibodies targeting the CSF1/CSF1R axis have shown promise in the treatment of TGCT and
cancer, with
pexidartinib recently receiving FDA approval for treatment of TGCT. Many small-molecule
kinase inhibitors of CSF1R also inhibit the closely related
kinases KIT, PDGFRA,
PDGFRB, and FLT3, thus CSF1R suppression may be limited by off-target activity and associated adverse events. Vimseltinib (DCC-3014) is an oral, switch control
tyrosine kinase inhibitor specifically designed to selectively and potently inhibit CSF1R by exploiting unique features of the switch control region that regulates
kinase conformational activation. In preclinical studies, vimseltinib durably suppressed CSF1R activity in vitro and in vivo, depleted macrophages and other CSF1R-dependent cells, and resulted in inhibition of
tumor growth and bone degradation in mouse
cancer models. Translationally, in a phase I clinical study, vimseltinib treatment led to modulation of
biomarkers of CSF1R inhibition and reduction in
tumor burden in TGCT patients.