Development of molecular targeted therapies for ovarian cancer with homologous recombination deficiency

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K09249
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Oda Katsutoshi 東京大学, 医学部附属病院, 教授 (30359608)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 卵巣癌 / 分子標的薬 / ゲノム解析

Outline of Final Research Achievements

The expression profiles of SMYD2 showed significant overexpression of SMYD2 in high-grade serous ovarian carcinomas (HGSOC). Inhibition of SMYD2 by a SMYD2 inhibitor, LLY-507, increased the number of apoptotic cells and showed additive effect with olaparib inHGSOC cells.
The numbers of predicted neoantigens (neoAgs) were lower in HR-proficient than HR-deficient tumors. However, 40% of the patients with HR-proficient tumors still had higher than median numbers of neoAgs. Patients with both high neoAg numbers and high HLA-class I expression had the best progression-free survival in HR-proficient HGSOC.
In mouse models, MDM2 inhibitor, DS-5272, significantly inhibited ascites production, and significantly improved overall survival. Furthermore, DS-5272 significantly decreased vascular endothelial growth factor concentrations in both sera and ascites. Combined DS-5272 and an mTOR inhibitor, everolimus, showed synergistic anti-tumor effect in clear cell carcinomas.

Free Research Field

婦人科腫瘍

Academic Significance and Societal Importance of the Research Achievements

卵巣癌におけるゲノム・エピゲノム異常に基づき、治療標的分子を同定し、新たな個別化医療につながる可能性のある知見を報告した。
相同組換修復と関連するような分子標的治療法は他がん種でも注目されており、卵巣高異型度漿液性癌における本研究成果に基づくサブタイプの同定や分子標的治療法の探索が、将来的な卵巣癌のPrecision Medicineの発展に寄与すると期待される。相同組換修復異常と関連する変異シグネチャーとの相関についての知見は、知財申請につなげており、新規の検査法につながることも期待される。