Phase I dose‐escalation trial to repurpose propagermanium, an oral CCL2 inhibitor, in patients with breast cancer

Abstract

The formation of premetastatic niches creates a fertile environment for the seeding of disseminated cancer cells in selected secondary organs. This is crucial for the development of metastasis in various malignancies, including breast cancer (BC). We previously reported that the loss of FBXW7 in bone marrow‐derived stromal cells promoted cancer metastasis by increasing the production of the chemokine CCL2, which attracts myeloid‐derived suppressor cells and macrophages to the premetastatic niche. Furthermore, treatment with the CCL2 inhibitor propagermanium (PG), which has been used in Japan as a therapeutic agent against chronic hepatitis B, was shown to block the enhancement of metastasis in FBXW7‐deficient mice through inhibiting the formation of premetastatic niches. Here, we describe a phase I dose‐escalation study of PG used as an antimetastatic drug for perioperative patients with primary BC. The primary end‐point was the percentage of patients who experience dose‐limiting toxicity. Twelve patients were enrolled in the study. Dose‐limiting toxicity was not observed, and the maximum dose was determined to be 90 mg/body/day. The serum concentrations of PG were nearly within the normal range in all observation days. We observed an inverse correlation between FBXW7 mRNA levels in blood and the serum concentrations of CCL2 and interleukin (IL)‐6, in agreement with our previous mouse model. Also, IL‐6 was downregulated in a PG dose‐dependent manner, as observed in mice. Thus, PG was given safely and it is expected to have antimetastatic potential in BC. This trial is registered in the UMIN Clinical Trials Registry as UMIN000022494.

MCP-1 Predicts Recurrent Cardiovascular Events in Patients with Persistent Inflammation

“…In fact, propagermanium, a drug used clinically for the treatment of chronic hepatitis in Japan, inhibits C-C chemokine receptor 2 function and reduces macrophage infiltration and atherosclerosis in Apolipoprotein E (ApoE) knockout mice [30]. This has recently been reported in a phase I dose escalation trial with propagermaium in patients with breast cancer [31] and a phase 2 trial with anti-MCP-1 (carlumab) in patients with idiopatic pulmonary fibrosis [32]. In addition, MLN1202, a specific humanized monoclonal antibody that interacts with CCR2-inhibiting MCP-1 binding, was used in a randomized, double-blind, placebo-controlled study in patients at risk for atherosclerotic cardiovascular disease (2 or more risk factors for atherosclerotic cardiovascular disease and circulating CRP >3 mg/L) [33].…”

Integrative Bioinformatics Analysis Reveals Potential Target Genes and TNFα Signaling Inhibition by Brazilin in Metastatic Breast Cancer Cells

“…The axis between TNFα signaling and CCL2 has also been studied, in which TNFα increases the expression of CCL2 in human proximal tubular epithelial cells via activation of MAPK signaling (Ho et al, 2008). A recent clinical trial of an inhibitor of CCL2, namely propagermanium, showed proper safety and efficacy in patients with metastatic breast cancer (Masuda et al, 2020). Taken together, CCL2 is a promising target for inhibiting breast cancer metastasis; however, the role of brazilin in metastasis-related to CCL2 and TNFα signaling needs to be explored further.…”

Drug repositioning in cancer: The current situation in Japan

“…Furthermore, we showed that the administration of a CCL2 inhibitor, PG, blocked the enhancement of metastasis by inhibiting the formation of premetastatic niches in a mouse model . Based on these findings, we conducted a phase I dose‐escalation study of PG administration as an antimetastatic drug for perioperative patients with primary breast cancer and showed that PG could be given safely (UMIN000022494) . In addition, Kikuchi et al demonstrated that PG has antitumor activity due to its effects on promoting natural killer cell maturation for patients with metastatic gastric or oral cancer .…”