Development of novel therapy for prostate cancer focusing on DNA damage response

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K09345
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56030:Urology-related
• Research Institution: Osaka University
• Principal Investigator: Ishizuya Yu 大阪大学, 大学院医学系研究科, 助教 (00783854)
• Co-Investigator(Kenkyū-buntansha): 植村 元秀 福島県立医科大学, 医学部, 特任教授 (40631015)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 前立腺癌 / DNA損傷応答

Outline of Final Research Achievements

We identified candidate genes involved in PARP inhibitor sensitivity in prostate cancer cells, and showed that functional repression of genes involved in base excision repair and DNA replication, as well as those involved in homologous recombination repair, which is known to be synthetically lethal to PARP, enhanced sensitivity to PARP inhibitors. DNA replication. Functional suppression of the identified genes significantly enhanced PARP inhibitor-induced DNA damage in prostate cancer cells, leading to apoptosis. In addition, dysfunction of TP53, which is mutated at a certain frequency in prostate cancer tissues, rendered prostate cancer cells resistant to PARP inhibitors, and the relationship between TP53 dysfunction and the effects of PARP inhibitors is being investigated using clinical samples.

Free Research Field

泌尿器科学

Academic Significance and Societal Importance of the Research Achievements

新規アンドロゲン受容体シグナル阻害薬などが使用可能となった現在でも去勢抵抗性前立腺癌の予後は不良である。相同組み換え修復欠損(Homologous recombination deficiency : HRD)症例に対してPARP阻害剤が有効であるが、その対象となるのは一部の症例のみであり、対象症例もいずれ治療抵抗性となることが課題である。本研究により新たに同定されたPARP阻害剤の感受性に関連する遺伝子は、新規治療標的あるいはPARP阻害剤耐性の予測因子として有望である。