జర్నల్ ఆఫ్ కార్సినోజెనిసిస్ & మ్యూటాజెనిసిస్

నైరూప్య

Prospective Anticancer Therapy for CCL2-CCR2 Pathway Inhibition using Propagermanium

Shojiro Kikuchi, Takahito Jomori

Cancer stromal interactions have an essential role in the development and progression of most cancers. Cancer cells utilize the host's immune system for growth, invasion, survival, and metastasis. Because the CCL2 (chemokine (C-C-motif) ligand 2–CCR2 (C-C chemokine receptor type 2 pathway consists of a major inflammatory chemokine and receptor, various studies have been conducted to suppress cancer metastasis via this pathway. Many studies have indicated that the migration of tumor-associated macrophages (TAM) and monocytic bone marrow-derived suppressor cells (Mo-MDSCs) from the bone marrow into the microenvironment known as the "niche", which utilizes the CCL2–CCR2 pathway, promotes cancer metastasis. In line with this strategy, CCL2-neutralizing antibody CNTO888 (Carlumab), anti-CCR2 antibody (MLN1202, plozalizumab), and CCR2 antagonist (CCX872-B) proceeded to phase 1 and 2 clinical trials in cancer patients. However, no sufficient therapeutic effects have yet been proved. We focused on propagermanium (PG; 3-oxygermylpropionic acid polymer, Serocion®), which is an existing drug for hepatitis B virus (HBV) and has both CCR2 inhibition and natural killer (NK) cell activation properties. We conducted a single-arm clinical trial in refractory cancer patients. In both gastric and oral cancer patients, there was a tendency to prolong the survival period, and two out of eight patients with gastric cancer showed complete remission of liver and lung metastases. We considered that PG suppressed the growth of metastatic cancer by inhibiting the CCL2–CCR2 pathway and exhibited antitumor activity by activating NK cells. PG is a promising drug as a CCR2 inhibitor and an immune modulator activating NK cells. We review the recent progress in the development of CCL2–CCR2 inhibitors and the therapeutic potential of NK cell activation in cancer patients.