Utilization of antimetabolite drugs for the treatment of high-risk neuroblastoma

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K07711
• 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: Kitasato University (2020-2022); Nagoya University (2019)
• Principal Investigator: Kiyonari Shinichi 北里大学, 医学部, 講師 (70570836)
• Co-Investigator(Kenkyū-buntansha): 西尾 信博 名古屋大学, 医学部附属病院, 特任講師 (00586430)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: 神経芽腫 / 合成致死 / MYCN

Outline of Final Research Achievements

Conventional anticancer drugs (e.g., platinum compounds) are used for the treatment of neuroblastoma patients with MYCN-amplification, and therefore, the development of a safe and effective therapeutic agent is desired. Thymidylate synthase inhibitors are widely used for colorectal cancers, however, their usefulness in neuroblastoma has not been well examined. Here, we investigated the efficacies of approved antifolates, methotrexate, pemetrexed, and raltitrexed (RTX), on neuroblastoma cell lines. Cell growth-inhibitory assay revealed that RTX showed a superior inhibitory activity against MYCN-amplified cell lines. Interestingly, RTX treatments induced DNA damage response in MYCN-amplified cells to a greater extent. We propose that the high DNA replication stress and elevated levels of DNA damage due to aberrant MYCN expression would be the cause of increased sensitivity to RTX.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

希少な小児がんである神経芽腫の治療には成人がん用の抗がん剤が用いられている。そのため、小児がんの特性を踏まえた安全かつ治療効果の高い新規治療法の開発が望まれている。本研究により、特に悪性度の高いMYCN遺伝子増幅タイプの神経芽腫細胞が既存の葉酸代謝拮抗剤に対して高い感受性を示すことが明らかとなった。MYCN遺伝子の増幅がみられる患者さんに対しては低用量の葉酸代謝拮抗剤で治療効果が得られる可能性が示された。