Targeting bromodomains as a novel therapeutic strategy for clear cell carcinoma of the ovary.

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K23904
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0901:Oncology and related fields
• Research Institution: Tohoku University
• Principal Investigator: Shigeta Shogo 東北大学, 医学系研究科, 大学院非常勤講師 (90842633)
• Project Period (FY): 2019-08-30 – 2021-03-31
• Keywords: 卵巣癌 / 明細胞癌 / 個別化医療 / エピゲノム

Outline of Final Research Achievements

Focusing on epigenomic regulators, we investigate therapeutic target candidates for clear cell carcinoma of the ovary (OCCC), one of the chemo-resistant subtypes in ovarian cancer. It was elucidated that functional interference of BET proteins BRD2/BRD3 strongly suppresses OCCC cell proliferation. We also identified several inhibitors which synergistically suppress OCCC cell growth in combination with BET inhibitors.
It was also revealed that the suppression of the function of CHD4 sensitizes OCCC cells to platinum agents, a key anti-cancer drug in the treatment of ovarian cancer.
In this study, we also attempted to develop OCCC organoids that recapitulate drug sensitivity of their original tumor. We were successful in short-term OCCC organoid maintenance. The synergistic drug interactions detected in this study is to be examined in organoid model after the optimization of the culture protocol for long-term stable maintenance.

Free Research Field

婦人科悪性腫瘍

Academic Significance and Societal Importance of the Research Achievements

卵巣明細胞癌は本邦で発症頻度が高い疾患であるが、卵巣癌で最も高頻度に見られる高異型度漿液性癌と比較して卵巣癌治療の第一選択薬であるプラチナ製剤に抵抗性を示すことが多い。卵巣癌で使用可能となったPARP阻害剤による治療効果も限定的である可能性が示唆されている。
本研究では卵巣明細胞癌で特に有効と考えられる新規治療標的タンパク質の同定に成功し、有効な薬剤の組み合わせについても検証を行った。同定したタンパク質の一部については阻害剤が開発され、ヒトでの臨床試験が進行中のものも含まれている。本研究結果は組織型に応じた治療戦略が確立されていない卵巣癌において新たな個別化医療の可能性を示唆するものである。