FTY720プロドラッグ(pro-FTY)がリンパ球減少を回避して乳がんの増殖を抑制することを明らかに～今後化学療法と併用することでさらなる相乗効果が生じる可能性にも期待～

2025-06-19 兵庫医科大学,理化学研究所,東京科学大学,大阪国際大

<関連情報>

• https://www.hyo-med.ac.jp/files/20250619/7f937c035e9ab63faceca52c4bdeafdcf7d60ac9.pdf
• https://aacrjournals.org/cancerrescommun/article/5/6/981/762997/An-Acrolein-Based-Drug-Delivery-System-Enables

アクロレインをベースとした薬物送達システムにより、リンパ球減少を伴わない乳癌における腫瘍特異的スフィンゴシン-1-リン酸標的療法が可能になる An Acrolein-Based Drug Delivery System Enables Tumor-Specific Sphingosine-1-Phosphate Targeting in Breast Cancer without Lymphocytopenia

Masayuki Nagahashi;Miki Komatsu;Sayaka Urano;Mamiko Kuroiwa;Yuria Takahashi;Koji Morimoto;Ambara R. Pradipta;Katsunori Tanaka;Yasuo Miyoshi
Cancer Research Communications  Published:June 18 2025
DOI:https://doi.org/10.1158/2767-9764.CRC-25-0023

Abstract

We developed a novel FTY720 prodrug (pro-FTY) that specifically inhibits sphingosine-1-phosphate signaling in cancer cells using a novel drug delivery system that reacts with acrolein. Our objective was to evaluate the efficacy and safety of pro-FTY in preclinical experiments. Ten breast cancer cell lines, two multidrug-resistant cell lines, and one normal mammary cell line were used to compare the IC₅₀ values of pro-FTY with those of other drugs. Patient-derived organoids (PDO) were established and utilized for IC₅₀ value comparisons. Drug efficacy was tested in mice bearing either syngeneic 4T1 cell tumors or patient-derived xenograft tumors, and blood analysis (including mass spectrometry) was performed. FTY720 and pro-FTY inhibited the survival of all breast cancer cell lines, including multidrug-resistant cells resistant to paclitaxel or doxorubicin. Unlike pro-FTY, FTY720 inhibited the survival of normal breast cell lines, suggesting that pro-FTY does not affect normal breast cells. Pro-FTY showed reproducible activity against multidrug-resistant PDOs, whereas paclitaxel and doxorubicin did not. Mass spectrometric analysis of pro-FTY–treated mice showed that FTY720 accumulated in tumors but was barely detectable in blood. Importantly, lymphocytopenia occurred in FTY720-treated mice but not in pro-FTY–treated mice. Furthermore, intravenous pro-FTY treatment significantly suppressed tumor growth in mice bearing patient-derived xenograft tumors generated from multidrug-resistant PDOs. In conclusion, pro-FTY inhibited breast cancer, including multidrug-resistant breast cancer, while avoiding lymphocytopenia, highlighting its clinical potential.

Significance:

Pro-FTY selectively inhibits sphingosine-1-phosphate signaling in cancer cells using a novel acrolein-responsive drug delivery system that reacts with acrolein. Pro-FTY does not inhibit normal cell growth, thus avoiding lymphocytopenia. Pro-FTY is effective against multidrug-resistant breast cancer with a unique mechanism of action, highlighting its translational and therapeutic potential.