2021 Fiscal Year Final Research Report
Establishment of a novel combination therapy of ATR inhibitor and BRD4 inhibitor targeting ARID1A mutated clear cell ovarian cancer
Project/Area Number |
20K18219
|
Research Category |
Grant-in-Aid for Early-Career Scientists
|
Allocation Type | Multi-year Fund |
Review Section |
Basic Section 56040:Obstetrics and gynecology-related
|
Research Institution | Osaka University |
Principal Investigator |
Kinose Yasuto 大阪大学, 医学系研究科, 助教 (90778531)
|
Project Period (FY) |
2020-04-01 – 2022-03-31
|
Keywords | 卵巣癌 / 明細胞癌 / ゲノム医療 / 個別化医療 / ARID1A / PDX / ATR / BRD4 |
Outline of Final Research Achievements |
Clear cell ovarian cancer (CCOC) is often resistant to standard chemotherapy agents and has limited treatment options. ARID1A is the most prevalent genomic mutation with approximately 50% of all CCOC harboring this mutation. As we reported that ATR inhibitor (ATRi) alone and BRD4 inhibitor (BRD4i) alone demonstrated significant anti-tumor effect in CCOC experimental models from our previous study, we hypothesize that a combination of ATRi+ BRD4i will especially target ARID1A-mutated CCOC. We tested the combination of ATRi+ BRD4i in CCOC cell lines and patient-derived xenograft mouse models and observed significant synergy tumor regression. We found that ATRi+ BRD4i would be a novel molecular-targeted therapy in CCOC in the future.
|
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 |
卵巣明細胞癌(CCOC)は、現在臨床において使用している抗がん剤に対する抵抗性症例が多く治療に難渋しており、新規治療法の開発が喫緊の課題である。本研究ではCCOCの約50%が持つARID1A変異という特徴に着目し、新規治療の開発を目指した。本研究成果にて、ATR阻害かつBRD4阻害併用療法は、ARID1A変異を持つCCOCに対して強い相乗的な抗腫瘍効果が示され、この併用療法がARID1A変異を持つCCOCへの新規治療法となる可能性が見出された。本研究成果を早期に臨床応用するべく、今後も研究ならびに臨床試験の準備を進めてゆく。
|