Development of G-quadruplex ligands that target cancer stem cells

2015 Fiscal Year Final Research Report

• Project/Area Number: 25290060
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: Japanese Foundation for Cancer Research
• Principal Investigator: Seimiya Hiroyuki 公益財団法人がん研究会, がん化学療法センター分子生物治療研究部, 部長 (50280623)
• Co-Investigator(Renkei-kenkyūsha): NAGASAWA Kazuo 東京農工大学, 大学院工学研究院生命工学専攻生命有機化学講座, 教授 (10247223) ; MATSUSAKA Satoshi 公益財団法人がん研究会, がん研有明病院消化器化学療法科, 医長 (00372665)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: がん幹細胞 / テロメア / 分子標的 / DNA損傷 / グアニン４重鎖 / 神経膠腫 / 複製 / 創薬

Outline of Final Research Achievements

This study aims to develop G4 ligands that stabilize G-quadruplex (G4), a specialized structure of nucleic acids, and establish their anti-proliferative effects on cancer stem cells and the underlying molecular mechanisms. We found that G4 ligands, such as telomestatin and its derivative, X, preferentially attack the cancer stem cells of intractable glioblastoma (GSC). Our observations suggest that single-stranded DNA formed during replication and transcription causes G4 formation, which is targeted by G4 ligands. As a molecular mechanism that could explain the higher sensitivity of GSCs to G4 ligands, GSCs exhibited excessive response to the drug-induced replication stress. X inhibited the growth of GSC-derived tumors explanted in mice. These observations are fundamental achievement for development of G4 ligands as anticancer drugs.

Free Research Field

腫瘍治療学