2020 Fiscal Year Final Research Report
Targeting Annexin A4 with antisense oligonucleotides improved platinum resistance of ovarian clear cell carcinoma
| Project/Area Number |
19K18695
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 56040:Obstetrics and gynecology-related
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| Research Institution | Osaka University |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2021-03-31
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| Keywords | ovarian cancer / clear cell carcinoma / bridged nucleic acid / antisense / platinum resistance / annexin A4 |
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| Outline of Final Research Achievements |
Recently, such as PARP inhibitors have emerged, various innovative treatments strategies have become available for platinum-sensitive ovarian cancer. However, platinum resistance is still the major issue. Enhanced expression level of annexin A4 (ANXA4) in ovarian clear cell carcinoma (CCC) have associated with chemoresistance of platinum drug. We made oligonucleic acid drugs synthesized with bridged nucleic acid as preclinical model to suppress ANXA4 expression. ANXA4 ASOs suppressed the levels of ANXA4 expression and significantly improved sensitivity to the platinum drugs, and increased intracellular platinum accumulation. In vivo model mice, we observed enhanced antitumor effect when the ANXA4 ASO was treated in combination with the cisplatin Thus, we demonstrated improvement of platinum drug resistance with administration of ANXA4 ASO both in vitro and in vivo by accumulating intracellular platinum drug. ANXA4 ASO will be a therapeutic option for the ovarian clear cell carcinoma.
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| Free Research Field |
婦人科腫瘍
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| Academic Significance and Societal Importance of the Research Achievements |
卵巣癌は本邦の婦人科癌で最も予後不良な疾患であり、特に治療の中心となるプラチナ製剤に対する耐性は大きな課題である。特に、本邦では、プラチナ耐性である明細胞癌の割合が高く、そのプラチナ耐性の克服は卵巣癌治療を考える上で重要な課題である。本研究では、プラチナ耐性を誘導すると考えられるAnx A4のアンチセンスを人工核酸を用いて作成し、その有効性を検討した。その結果、作成したアンチセンスはin vitro, in vivoいずれにおいてもプラチナ抵抗性を改善し、プラチナ製剤と併用することで抗腫瘍効果を増強した。今後、組織移行性などの課題を解決し、創薬に向けてさらなる研究を進める予定である。
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