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

Research Project

Project/Area Number 19H03497
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 50010:Tumor biology-related
Research InstitutionTokyo 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
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2021: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2020: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Fiscal Year 2019: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
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 / 合成致死療法 / DNA相同組換え修復 / 乳がん / BRCA1遺伝子 / BRCA2遺伝子 / BRCA1, 2 / 合成致死 / DNA相同組換え修復機能
Outline of Research at the Start

BRCA変異陽性乳がんのPARP阻害剤による合成致死療法では、PARP阻害剤耐性獲得が問題となっている。そこで、DNA2本鎖切断の相同組換え修復機能(HR)の抑制による耐性克服療法を開発し、その一般乳がんへの展開を目的とする。頻度の高い耐性獲得機序に、BRCA変異細胞におけるHR機能の回復がある。そこで、HR関連分子を抑制、再度、HRを低下させ、感受性を回復させる。この治療法は、耐性獲得症例のみならず、最初からHRが維持されPARP阻害剤無効な多くの乳がんにも有効な可能性があり、この相同組換え修復機能を標的とした新規合成致死療法の開発は、がん治療に大きく貢献することが期待される。

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.

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。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • Research Products

    (27 results)

All 2022 2021 2020 2019 Other

All Journal Article (15 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 14 results,  Open Access: 11 results) Presentation (11 results) (of which Int'l Joint Research: 2 results,  Invited: 8 results) Remarks (1 results)

  • [Journal Article] Regulation of Intrinsic Functions of PD-L1 by Post-Translational Modification in Tumors.2022

    • Author(s)
      Nihira NT, Miki Y.
    • Journal Title

      Front Oncol.

      Volume: 12 Pages: 825284-825284

    • DOI

      10.3389/fonc.2022.825284

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The BRCA2 missense mutation K2497R suppressed self-degradation and increased ATP production and cell proliferation.2022

    • Author(s)
      Enkhbat G, Nakanishi A, Miki Y.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 590 Pages: 27-33

    • DOI

      10.1016/j.bbrc.2021.12.073

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] BRCA2 represses the transcriptional activity of pS2 by E2-ERα.2022

    • Author(s)
      Fukuda M, Tojo Y, Sato A, Saito H, Nakanishi A, Miki Y.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 588 Pages: 75-82

    • DOI

      10.1016/j.bbrc.2021.12.054

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 総論 遺伝性腫瘍総論2022

    • Author(s)
      三木 義男
    • Journal Title

      遺伝子医学【遺伝性腫瘍学入門 遺伝性腫瘍の基礎知識】

      Volume: 別冊 Pages: 22-30

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Integrative cancer genomics in the era of precision cancer medicine.2021

    • Author(s)
      Inazawa J, Miki Y, Nakamura Y.
    • Journal Title

      J Hum Genet.

      Volume: 66 Issue: 9 Pages: 843-843

    • DOI

      10.1038/s10038-021-00970-6

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] CDK1 inhibitor controls G2/M phase transition and reverses DNA damage sensitivity.2021

    • Author(s)
      Sunada S, Saito H, Zhang D, Xu Z, Miki Y.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 550 Pages: 56-61

    • DOI

      10.1016/j.bbrc.2021.02.117

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries2021

    • Author(s)
      Gharahkhani Puya、et al. (Tamiya Gen; 44th in 86 authors)
    • Journal Title

      Nature Communications

      Volume: 12 Issue: 1 Pages: 1258-1258

    • DOI

      10.1038/s41467-020-20851-4

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Pathogenicity assessment of variants for breast cancer susceptibility genes based on BRCAness of tumor sample2021

    • Author(s)
      Yoshida R, Hagio T, Kaneyasu T, Gotoh O, Osako T, Tanaka N, Amino S, Yaguchi N, Nakashima E, Kitagawa D, Ueno T, Ohno S, Nakajima T, Nakamura S, Miki Y, Hirota T, Takahashi S, Matsuura M, Noda T, Mori S.
    • Journal Title

      Cancer Sci.

      Volume: 112(3) Issue: 3 Pages: 1310-1319

    • DOI

      10.1111/cas.14803

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Ultradeep targeted sequencing of circulating tumor DNA in plasma of early and advanced breast cancer2020

    • Author(s)
      Chin Yoon Ming、Takahashi Yoko、Chan Hiu Ting、Otaki Masumi、Fujishima Makoto、Shibayama Tomoko、Miki Yoshio、Ueno Takayuki、Nakamura Yusuke、Low Siew‐Kee
    • Journal Title

      Cancer Science

      Volume: 112 Issue: 1 Pages: 454-464

    • DOI

      10.1111/cas.14697

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Acetylation-dependent regulation of PD-L1 nuclear translocation dictates the efficacy of anti-PD-1 immunotherapy2020

    • Author(s)
      Gao Y, Nihira NT, Bu X, Chu C, Zhang J, Kolodziejczyk A, Fan Y, Chan NT, Ma L, Liu J, Wang D, Dai X, Liu H, Ono M, Nakanishi A, Inuzuka H, North BJ, Huang YH, Sharma S, Geng Y, Xu W, Liu XS, Li L, Miki Y, Sicinski P, Freeman GJ, Wei W.
    • Journal Title

      Nat Cell Biol.

      Volume: 22(9) Issue: 9 Pages: 1064-1075

    • DOI

      10.1038/s41556-020-0562-4

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Prevalence of disease-causing genes in Japanese patients with BRCA1/2-wildtype hereditary breast and ovarian cancer syndrome2020

    • Author(s)
      Kaneyasu T, Mori S, Yamauchi H, et al.
    • Journal Title

      NPJ Breast Cancer.

      Volume: 6 Issue: 1 Pages: 25-25

    • DOI

      10.1038/s41523-020-0163-1

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Estradiol/GPER affects the integrity of mammary duct-like structures in vitro.2020

    • Author(s)
      Deng Y, Miki Y*, Nakanishi A.
    • Journal Title

      Sci Rep.

      Volume: 10 Issue: 1 Pages: 1386-1386

    • DOI

      10.1038/s41598-020-57819-9

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of two novel breast cancer loci through large-scale genome-wide association study in the Japanese population2019

    • Author(s)
      Low Siew-Kee、Chin Yoon Ming、Ito Hidemi、Matsuo Keitaro、et al.
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1 Pages: 17332-17332

    • DOI

      10.1038/s41598-019-53654-9

    • NAID

      120006875665

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Non-V600E BRAF mutations and EGFR signaling pathway in colorectal cancer.2019

    • Author(s)
      Osumi H, Shinozaki E, Wakatsuki T, Suenaga M, Ichimura T, Ogura M, Takahari D, Ooki A, Suzuki T, Ota Y, Nakayama I, Chin K, Miki Y, Yamaguchi K.
    • Journal Title

      Int J Cancer.

      Volume: 145 Issue: 9 Pages: 2488-2495

    • DOI

      10.1002/ijc.32320

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 遺伝性腫瘍 遺伝子バリアント解釈の問題点2019

    • Author(s)
      三木義男
    • Journal Title

      腫瘍内科

      Volume: 24 Pages: 370-377

    • Related Report
      2019 Annual Research Report
  • [Presentation] 遺伝性乳がん原因遺伝子BRCA2タンパク質の核輸送システムの解明2021

    • Author(s)
      平山 栞, 佐藤 亜美, トウ・ウ , 中西 啓, 三木 義男
    • Organizer
      第80回 日本癌学会学術総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 臨床的意義不明なBRCA2バリアントの相同組換え活性2021

    • Author(s)
      郭 倩倩, 徐 澤宇, 斉藤 広子, 砂田 成章, 三木 義男
    • Organizer
      第80回 日本癌学会学術総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] S期における中心体隣接の生理的役割2021

    • Author(s)
      東條 陽, 中西 啓, 三木 義男
    • Organizer
      第80回 日本癌学会学術総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] PD-L1の核内移行制御に対する分子標的薬は抗PD抗体による癌免疫治療の効果を向上させる2021

    • Author(s)
      仁平 直江, 三木 義男, Wei Wenyi
    • Organizer
      第80回 日本癌学会学術総会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 遺伝子修復を標的とする新しい治療法の開発2020

    • Author(s)
      三木 義男, 砂田 成章, 中西 啓
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 遺伝性乳がんの分子標的治療-現状と将来展望-2019

    • Author(s)
      三木義男、中西 啓
    • Organizer
      第119回日本外科学会定期学術集会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Familial Cancer - Molecular Basis and its Implications for Clinical Practice -2019

    • Author(s)
      Yoshio Miki
    • Organizer
      the 78th Annual Meeting of the Japanese Cancer Association
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] BRCA VUSに対する機能的評価の取り組み2019

    • Author(s)
      三木義男
    • Organizer
      第 27 回 日本乳癌学会学術総会、
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] ゲノム情報を基盤としたこれからの乳がん治療2019

    • Author(s)
      三木義男
    • Organizer
      第 27 回 日本乳癌学会学術総会、
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] BRCA1 and BRCA2 responsible for HBOC: molecular mechanisms and clinical impact in cancer therapy2019

    • Author(s)
      Yoshio Miki
    • Organizer
      Academic Session, National Institute of Genomic Medicine, Mexico
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] BRCA1 and BRCA2 responsible for HBOC: molecular mechanisms and clinical impact in cancer therapy2019

    • Author(s)
      Yoshio Miki
    • Organizer
      6th Annual Meeting, DEL COLEGIO MEXICANO PARA, LA INVESTIGACION DEL CANCER
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Remarks] 東京医科歯科大学 難治疾患研究所 分子遺伝分野

    • URL

      http://www.tmd.ac.jp/mri/mgen/index.html

    • Related Report
      2019 Annual Research Report

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Published: 2019-04-18   Modified: 2023-01-30  

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