<p>Pexidartinib, a Novel Small Molecule CSF-1R Inhibitor in Use for Tenosynovial Giant Cell Tumor: A Systematic Review of Pre-Clinical and Clinical Development</p>

Abstract

Tenosynovial giant cell tumor (TGCT) is a rare benign tumor that involves the synovium, bursa, and tendon sheath, resulting in reduced mobility of the affected joint or limb. The current standard of care for TGCT is surgical resection. However, some patients have tumor recurrence, present with unresectable tumors, or have tumors that are in locations where resection could result in amputations or significant debility. Therefore, the development of systemic agents with activity against TGCT to expand treatment options is a highly unmet medical need. Pathologically, TGCT is characterized by the overexpression of colonystimulating factor 1 (CSF-1), which leads to the recruitment of colony-stimulating factor-1 receptor (CSF-1R) expressing macrophages that make up the primary cell type within these giant cell tumors. The binding of CSF-1 and CSF-1R controls cell survival and proliferation of monocytes and the switch from a monocytic to macrophage phenotype contributing to the growth and inflammation within these tumors. Therefore, molecules that target CSF-1/CSF-1R have emerged as potential systemic agents for the treatment of TGCT. Given the role of macrophages in regulating tumorigenesis, CSF1/CSF1R-targeting agents have emerged as attractive therapeutic targets for solid tumors. Pexidartinib is an orally bioavailable and potent inhibitor of CSF-1R which is one of the most clinically used agents. In this review, we discuss the biology of TGCT and review the pre-clinical and clinical development of pexidartinib which ultimately led to the FDA approval of this agent for the treatment of TGCT as well as ongoing clinical studies utilizing pexidartinib in the setting of cancer.

The Tumor Microenvironment in SCC: Mechanisms and Therapeutic Opportunities

“…In a syngeneic mouse model of melanoma, pexidartinib, a potent inhibitor of the CSF-1 receptor (CSF-1R), conferred anti-tumoral response associated with TAMs reduction ( Mok et al, 2014 ; Figure 2F ). Pexidartinib is approved for the treatment of tenosynovial giant cell tumor ( Lamb, 2019 ) and is currently being tested in several clinical trials, none of them for SCC but with great potential ( Benner et al, 2020 ). CCL2, also known as MCP-1, is another monocyte chemoattractant that promotes carcinogenesis by recruiting TAMs and inducing immune evasion through PD-1 signaling ( Yang et al, 2020 ; Figure 2E ).…”

Repurposing Known Drugs as Covalent and Non-covalent Inhibitors of the SARS-CoV-2 Papain-Like Protease

“…Pexidartinib is a tyrosine kinase inhibitor recently approved by the FDA for the treatment of adults with symptomatic tenosynovial giant cell tumor (Benner et al, 2020 ). In particular, it works by inhibiting the colony-stimulating factor 1 receptor (Benner et al, 2020 ).…”

“…Pexidartinib is a tyrosine kinase inhibitor recently approved by the FDA for the treatment of adults with symptomatic tenosynovial giant cell tumor (Benner et al, 2020 ). In particular, it works by inhibiting the colony-stimulating factor 1 receptor (Benner et al, 2020 ). Interestingly, pexidartinib returned an MM-GBSA–binding free energy comparable to that of dasatinib and a top-scored docking pose showing a binding mode in good agreement with that of VIR251 (TC-IFP = 0.582).…”

Chemically‐Induced Cross‐Linking of Peptidic Fibrils for Scaffolding Polymeric Particles and Macrophages

“…Indeed, many recently discovered kinase inhibitors are classified as BCS II compounds. [ 53–63 ] Another advantage is that, depending on the size of the particles and locations, subcutaneously administered micro‐ and nanoparticles tend to drain into the lymphatics, thus resulting in unpredictable local drug concentrations at the intended site of action and potential absorption into the systemic vasculature. Therefore, clEAK is a potential platform for delivering drug‐loaded particles and cells in vivo for sustained release.…”