Tumor-associated macrophages, itraconazole

Malignant tumors

We have reported clinical and basic studies focusing on the cross-organ antitumor effect of itraconazole, an antifungal drug. Clinical studies have suggested that itraconazole improves prognosis in multiple cancer types (2014-2022). In addition, basic studies using cervical cancer and endometrial cancer cell lines have shown that itraconazole suppresses abnormally elevated Akt/mTOR and Hedgehog signaling, thereby suppressing tumor growth (2016-2017). We also confirmed its effect on intracellular lipid transport and cell membrane phospholipid composition (2022-2023). At the same time, other institutions also reported clinical studies showing improved prognosis, signal suppression effects in cancer cells, inhibition of angiogenesis and lymphangiogenesis, and antitumor effects mediated by cancer-associated fibroblasts.
Since 2015, we have been conducting translational research (WOO study) to discover biomarkers and clarify the mechanism of action of itraconazole for solid tumors. This was implemented at our hospital as a catch-up study for cancer gene panel testing, which became eligible for insurance coverage in 2019, and we have reported the improved prognosis of the targeted treatment group, including those enrolled in the WOO study (2023). Based on lipid analysis in basic research and interim analysis in the WOO study (tissue genome and expression variation analysis) (2018), we focused on tumor-associated macrophages (TAM) and reported that itraconazole suppresses cancer growth by transforming M2 TAM, which is involved in tumor growth, into M1 TAM, which attacks tumors (2023).

Focusing on tumor-associated macrophages (TAM), itraconazole was shown to suppress cancer growth by transforming M2 TAM, which is involved in tumor growth, into M1 TAM, which attacks tumors.

• Conducted the World Oral Organisation (WOO) trial, the largest number of trials in the world, in research into itraconazole as a cancer treatment, and has samples from the trial.
• In addition to biomarker discovery, we comprehensively explore genomes, proteins, and metabolites for novel therapeutic targets.

Currently, immunotherapy drugs on the market are only about 20% effective, making the development of combination drugs an urgent task.

It is also expected that this will lead to the development of a new targeted treatment for TAM.

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1. Takimoto Y, Tsubamoto H, et al. Itraconazole modulates phospholipid levels in tumor-associated macrophages. Anticancer Res. 2023, 43 (5) 1981-1984
2. Ueda T, Tsubamoto H, et el. Comprehensive Genomic Profiling Detects Hereditary Cancers and Confers Survival Advantage in Patients With Gynaecological Cancers. Anticancer Res. 2023, 43 (5) 2091-2101
3. Takimoto Y, Tsubamoto H, et al. Itraconazole Repolarizes Tumor-associated Macrophages and Suppresses Cervical Cancer Cell Growth. Anticancer Res. 2023 Feb;43(2):569-580
4. Sawasaki M, Tsubamoto H, et al. First-Line Gemcitabine, Nab-Paclitaxel, and Oxaliplatin Chemotherapy With Itraconazole in Patients With Metastatic Pancreatic Cancer: A Single Institution Experience. Anticancer Res. 2022, 42 (12) 6063-6069
5. Isono R, Tsubamoto H, et al. Itraconazole Inhibits Intracellular Cholesterol Trafficking and Decreases Phosphatidylserine Level in Cervical Cancer Cells. Anticancer Res. 2021, 41 (11) 5477-5480

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