Development of amplified gene-selective alkylator as a novel cancer therapeutic agent

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07767
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Chiba Cancer Center (Research Institute)
• Principal Investigator: Takatori Atsushi 千葉県がんセンター(研究所), がん治療開発グループ がん先進治療開発研究室, 室長 (40455390)
• Co-Investigator(Kenkyū-buntansha): 渡部 隆義 千葉県がんセンター(研究所), がん研究開発グループ, 研究員 (60526060)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 増幅遺伝子 / ピロール・イミダゾール・ポリアミド化合物 / アルキル化剤 / ケミカルバイオロジー

Outline of Final Research Achievements

Copy number amplification of oncogenes is involved in tumor development although targeting amplified genomic sequences has been a therapeutic challenge. We have developed an alkylating pyrrole-imidazole polyamide compound (PIP-seco-CBI), that sequence-selectively targets the amplified MYCN gene in MYCN-amplified neuroblastoma cells. In this study, we found that, after the compound treatment, DNA damage was increased at the amplified region where DNA damage repair-related proteins were accumulated. Inhibition of DNA damage response pathways induced an accumulation of DNA damage by the PIP compound and sensitized MYCN-amplified neuroblastoma cells to the compound, suggesting a novel amplification-targeting therapeutic strategy for cancers with oncogene-amplifications.

Free Research Field

腫瘍生物学　実験動物学

Academic Significance and Societal Importance of the Research Achievements

がん分子標的薬開発ではキナーゼ阻害剤の開発が進んできた一方で、小分子化合物では標的としにくいundruggableな転写因子などに対する薬剤開発は十分ではない。本研究をさらに進めることで、増幅遺伝子を直接傷害することによって起こるゲノム構造変化を明らかにし、種々の増幅がん遺伝子を標的とした新しい治療法開発につなげることができれば、個々の発がん原因を考慮した治療選択が可能となる個別化医療を日本から提案できるものと期待される。