TY - JOUR
T1 - Phase I dose-escalation trial to repurpose propagermanium, an oral CCL2 inhibitor, in patients with breast cancer
AU - Masuda, Takaaki
AU - Noda, Miwa
AU - Kogawa, Takahiro
AU - Kitagawa, Dai
AU - Hayashi, Naoki
AU - Jomori, Takahito
AU - Nakanishi, Yoichi
AU - Nakayama, Keiichi I.
AU - Ohno, Shinji
AU - Mimori, Koshi
N1 - Funding Information:
This study was supported by AMED (Translational Research Network Program) of the Japan Agency for Medical Research and Development (grant no. 16ck0106160h0002). Propagermanium was kindly provided by Sanwa Kagaku Kenkyusho Co., Ltd. (Nagoya, Japan). We thank Atsushi Kishimoto, Naomi Takayanagi, Makiko Uchiyama and other staff of the Center for Clinical and Translational Research, Kyushu University Hospital, for data collection, analysis, and interpretation, as well as helpful advice. We thank Dr Yusuke Tsuruda and Dr Tyler Lahusen for helpful comments and English proofreading. We also thank Dr Norihiro Hirata of the Academic Research and Industrial Collaboration Management Office of Kyushu University for conducting this study, and N. Mishima and T. Kawano for their excellent technical assistance. This work was supported in part by the following grants and foundations: Japan Agency for Medical Research and Development (16ck0106160h0002, 18ae0101016, 18cm0106504, 18kk0205003, and 18ck0106259); Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Science Research (19H03715, 19K09176, 16K09220, 19K18057, 18K08649, 18K15323, 15H05912, 15H05707 and 15H05791); JST AIP-PRISM (JPMJCR18Y5); OITA Cancer Research Foundation; and Priority Issue on Post-K computer (hp170227, hp160219, and hp170227).
Funding Information:
This study was supported by AMED (Translational Research Network Program) of the Japan Agency for Medical Research and Development (grant no. 16ck0106160h0002). Propagermanium was kindly provided by Sanwa Kagaku Kenkyusho Co., Ltd. (Nagoya, Japan). We thank Atsushi Kishimoto, Naomi Takayanagi, Makiko Uchiyama and other staff of the Center for Clinical and Translational Research, Kyushu University Hospital, for data collection, analysis, and interpretation, as well as helpful advice. We thank Dr Yusuke Tsuruda and Dr Tyler Lahusen for helpful comments and English proofreading. We also thank Dr Norihiro Hirata of the Academic Research and Industrial Collaboration Management Office of Kyushu University for conducting this study, and N. Mishima and T. Kawano for their excellent technical assistance. This work was supported in part by the following grants and foundations: Japan Agency for Medical Research and Development (16ck0106160h0002, 18ae0101016, 18cm0106504, 18kk0205003, and 18ck0106259); Japan Society for the Promotion of Science (JSPS) Grant‐in‐Aid for Science Research (19H03715, 19K09176, 16K09220, 19K18057, 18K08649, 18K15323, 15H05912, 15H05707 and 15H05791); JST AIP‐PRISM (JPMJCR18Y5); OITA Cancer Research Foundation; and Priority Issue on Post‐K computer (hp170227, hp160219, and hp170227).
Publisher Copyright:
© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
PY - 2020/3/1
Y1 - 2020/3/1
N2 - 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.
AB - 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.
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U2 - 10.1111/cas.14306
DO - 10.1111/cas.14306
M3 - Article
C2 - 31943636
AN - SCOPUS:85079425754
VL - 111
SP - 924
EP - 931
JO - Cancer Science
JF - Cancer Science
SN - 1347-9032
IS - 3
ER -