2021 Fiscal Year Final Research Report
Development of Novel Therapeutic Approach Exploiting Constitutive DNA Damage in Genitourinary Cancer
| Project/Area Number |
19K18624
|
|---|
| Research Category |
Grant-in-Aid for Early-Career Scientists
|
| Allocation Type | Multi-year Fund |
|---|
| Review Section |
Basic Section 56030:Urology-related
|
|---|
| Research Institution | Osaka Medical and Pharmaceutical University |
|---|
Principal Investigator |
|
|---|
| Project Period (FY) |
2019-04-01 – 2022-03-31
|
| Keywords | 泌尿器がん / DNAダメージ |
|---|
| Outline of Final Research Achievements |
There has been accumulating evidence for the clinical benefit of chemoradiation therapy (CRT), whereas mechanisms in CRT-recurrent clone derived from the primary tumor are still elusive. Herein, we identified an aberrant BUB1B/BUBR1 expression in CRT-recurrent clone in bladder cancer (BC). CRT-recurrent BC cells exhibited a cell-cycle independent upregulation of BUB1B/BUBR1 expression rendering an enhanced DNA repair activity in response to DNA double strand breaks (DSBs). We revealed that cells with aberrant BUB1B/BUBR1 expression dominantly exploit mutagenic non-homologous end joining (NHEJ). We further found that phosphorylated ATM interacts with BUB1B/BUBR1 after ionizing radiation (IR) treatment. In vivo, tumor growth of CRT-resistant T24R cells was abrogated by ATM inhibition using AZD0156. These data collectively suggest a redundant role of BUB1B/BUBR1 underlying mutagenic NHEJ in an ATM-dependent manner.
|
| Free Research Field |
尿路上皮がん
|
| Academic Significance and Societal Importance of the Research Achievements |
現在国内で行われているゲノム医療の普及促進の一つの課題として、解析後のアウトプットとなる臨床治験を含む治療選択肢の拡充が挙げられると申請者らは考えている。癌治療、研究において特定のKey Moleculeによる多彩な形質変化を明らかにすることは、患者様の発現差異による層別化を可能にし、さらにその変化に伴う治療ターゲットの発見がテーラーメード医療を可能にする。本研究においても治療効果予測因子であるバイオマーカーを明らかにすることにより、より精度が高く、Precision Medicineへの発展を目指すとともに、ゲノム医療で加療選択され得る治療オプションの一つとなる可能性を明らかにする。
|
