Exploring the mechanism of peritoneal dissemination and development of a new molecular targeted therapy by using orthotopic ovarian cancer patient-derived xenograft mouse models

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K23003
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0906:Surgery related to the biological and sensory functions and related fields
• Research Institution: Osaka University
• Principal Investigator: Miyamoto Mayuko 大阪大学, 医学系研究科, 招へい教員 (70880988)
• Project Period (FY): 2020-09-11 – 2022-03-31
• Keywords: 卵巣癌 / 腹膜播種 / PDX / ゲノム医療 / 個別化医療 / CCNE1 / WEE1 / ATR

Outline of Final Research Achievements

Advanced ovarian cancer often shows peritoneal carcinomatosis that is difficult to control and related to poor prognosis. To find the mechanism of peritoneal carcinomatosis and develop a novel treatment, we established a patient-derived xenograft (PDX) ovarian cancer mouse model, WO-77. This PDX mouse model faithfully recapitulates human advanced-stage ovarian cancer peritoneal carcinomatosis. From sequencing analysis with WO-77 cancer tissue, we found that WO-77 harbored CCNE1 gene amplification. We treated the WO-77 PDX mice with WEE1 inhibitor and ATR inhibitor, resulting in a significant anti-tumor effect, decreased ascites volume, and prolonged survival. In conclusion, this study demonstrates the dual blockade of WEE1 and ATR could be a novel therapeutic option for advanced ovarian cancer.

Free Research Field

婦人科癌、卵巣癌、分子標的治療、ゲノム医療、個別化医療

Academic Significance and Societal Importance of the Research Achievements

卵巣がんに特徴的である腹膜播種の機序解明・新規治療法の確立を目指して、ヒト卵巣がんの腹膜播種進展を忠実に再現する患者由来腫瘍異種移植卵巣同所移植マウスモデルを確立した。このマウスモデルとがんの遺伝子解析を組み合わせることで、卵巣がん腹膜播種を制御しうる新規治療法を同定した。本研究成果を臨床応用するために、米国にてヒトでの臨床試験を準備している。また、この腹膜播種マウスモデルを用いて今後もさらなる腹膜播種進展機構の解明と新規標的治療の開発研究を行っていく。