Development of a Novel Synthetic Lethal Therapy for Breast Cancer by Targeting DNA Homologous Recombination Repair.

2021 Fiscal Year Final Research Report

• Project/Area Number: 19H03497
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Miki Yoshio 東京医科歯科大学, 難治疾患研究所, 教授 (10281594)
• Co-Investigator(Kenkyū-buntansha): 砂田 成章 東京医科歯科大学, 難治疾患研究所, 助教 (70807677)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 合成致死量法 / BRCA1, BRCA2 / 相同組み換え修復 / PARP阻害剤 / 耐性克服療法

Outline of Final Research Achievements

Acquisition of PARP inhibitor resistance is a problem in synthetic lethal therapy with PARP inhibitors for BRCA mutation-positive breast cancer. Therefore, the aim of this project is to develop a therapy to overcome resistance by inhibiting the homologous recombination (HR) repair function of DNA double-strand breaks to restore PARP inhibitor sensitivity. Here, the key issue is the development of a method to inhibit HR repair capacity. In this study, we found that BRCA2 migrates to the nucleus through interaction with KPNA7, and that inhibition of KPNA7 prevents BRCA2 nuclear transport and HR repair in the nucleus. Furthermore, we found MG-1 and MG-2 (tentative name) as KPNA7 inhibitors by screening KPNA7 inhibitor compounds using a library of compounds with known functions.

Free Research Field

分子腫瘍学

Academic Significance and Societal Importance of the Research Achievements

BRCA変異陽性乳がんのPARP阻害剤による合成致死療法が開始されたが、PARP阻害剤耐性獲得が問題となっている。そこで、この耐性克服療法の開発を目的に、BRCA2の輸送経路情報を基盤にした戦略による阻害候補分子、及び化合物ライブラリースクリーニングによる阻害化合物の同定は、遺伝性乳がん卵巣がん症候群（HBOC）患者に対する有効な治療法開発に繋がり、医学的意義は大きい。また、最初からHR機能が維持されPARP阻害剤のみでは無効な多くの乳がんにも有効である可能性があり、本研究成果は新規乳がん治療法の開発に繋がり、がん医療に大きく貢献することが期待され、医学的・社会的貢献度も高い。