Effects of regorafenib on the mononuclear/phagocyte system and how these contribute to the inhibition of colorectal tumors in mice

Abstract

Background Regorafenib was previously shown to reduce tumor-associated macrophages and potently inhibit colony-stimulating factor 1 receptor (CSF1R), also known as CD115, in biochemical assays. The CSF1R signaling pathway is essential in the biology of the mononuclear/phagocyte system, which itself can promote the development of cancer. Methods A deeper investigation of regorafenib’s effects on CSF1R signaling was performed using preclinical in vitro and in vivo studies with syngeneic CT26 and MC38 mouse models of colorectal cancer. Peripheral blood and tumor tissue were analyzed mechanistically by flow cytometry using antibodies against CD115/CSF1R and F4/80 and by ELISA for chemokine (C-C motif) ligand 2 (CCL2) levels. These read-outs were correlated with drug levels for the detection of pharmacokinetic/pharmacodynamic relationships. Results Potent inhibition of CSF1R by regorafenib and its metabolites M-2 and M-5 was confirmed in vitro in RAW264.7 macrophages. The dose-dependent growth inhibition of subcutaneous CT26 tumors by regorafenib was associated with a significant reduction in both the number of CD115hi monocytes in peripheral blood and the number of selective subpopulations of intratumoral F4/80hi tumor-associated macrophages. CCL2 levels in blood were not affected by regorafenib but increased in tumor tissue, which may contribute to drug resistance and prevent complete tumor remission. An inverse relationship between regorafenib concentration and the number of CD115hi monocytes and CCL2 levels was observed in peripheral blood, supporting the mechanistic involvement of regorafenib. Conclusions These findings may be clinically useful in optimizing drug dosing by blood-based pharmacodynamic markers, and in identifying resistance mechanisms and ways to overcome them by appropriate drug combinations.

Large-scale, prospective observational study of regorafenib in Japanese patients with advanced gastrointestinal stromal tumors in a real-world clinical setting

“…PDGFR and fibroblast growth factor receptor), angiogenesis (e.g. VEGFR 1-3 and TIE2) (3,5), and tumor immunity (6). Its efficacy was demonstrated in the phase 3 GRID trial, in which it significantly improved progression-free survival (primary endpoint) and the disease control rate (DCR) compared with placebo in patients with metastatic and/or unresectable GIST that had progressed after treatment with imatinib and sunitinib (7).…”

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“…PDGFR and fibroblast growth factor receptor), angiogenesis (e.g. VEGFR 1-3 and TIE2) (3,5), and tumor immunity (6). Its efficacy was demonstrated in the phase 3 GRID trial, in which it significantly improved progression-free survival (primary endpoint) and the disease control rate (DCR) compared with placebo in patients with metastatic and/or unresectable GIST that had progressed after treatment with imatinib and sunitinib (7).…”