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: Komura Kazumasa 大阪医科薬科大学, 医学部, 講師 (10789853)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Discontinued (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 泌尿器がん / DNAダメージ / 泌尿生殖器腫瘍

Outline of Research at the Start

申請者は、現在までにがんのエピゲノム解析から、ある特定の遺伝子変異等からの最終的なアウトプットのPhenotypeとして、がん細胞に恒常的なDNAダメージ負荷をもつサブセットが存在することを報告している。本研究課題では、この恒常的DNAダメージ負荷をもつがん細胞が特異的に依存するATRシグナルを治療ターゲットとすることにより、正常細胞には影響を与えずに、がん細胞のみに合成致死効果を誘導するための革新的な新規治療戦略の開発を目指すとともに、臨床応用のためのバイオマーカーを同定する。

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.

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。

Research Products

• [Int'l Joint Research] Memorial Sloan Kettering Cancer Center(米国)
• [Journal Article] Early Prostate-Specific Antigen (PSA) Change at Four Weeks of the First-Line Treatment Using Abiraterone and Enzalutamide Could Predict Early/Primary Resistance in Metastatic Castration-Resistant Prostate Cancer. (2021)
  • Author(s): Uchimoto T,Komura K, Fukuokaya W, Kimura T, Takahashi K, Nishimura K, Nakamori K, Fujiwara Y, Matsunaga T, Tsutsumi T, Tsujino T, Maenosono R, Yoshikawa Y, Taniguchi K, Tanaka T, Uehara H, Ibuki N, Hirano H, Nomi H, Takahara K, Inamoto T, Egawa S, Azuma H.
  • Journal Title: Cancers Volume: 13 Issue: 3 Pages: 2-12
  • DOI: 10.3390/cancers13030526
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Risk Stratification for the Prediction of Overall Survival Could Assists Treatment Decision Making at the Diagnosis of Castration-Resistant Prostate Cancer - a Multicenter Collaborative Study in Japan. (2020)
  • Author(s): Uchimoto T,Komura K, Fukuokaya W, Kimura T, Takahashi K, Fujiwara Y,Matsunaga T, Tsutsumi T, Tsujino T, Taniguchi K, Tanaka T, Uehara H, Ibuki N, Hirano H, Nomi H, Takahara K, Inamoto T, Egawa S, Azuma H.
  • Journal Title: BJU Int Volume: 127 Issue: 2 Pages: 212-21
  • DOI: 10.1111/bju.15187
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Adjuvant chemotherapy improves overall survival in patients with localized upper tract urothelial carcinoma harboring pathologic vascular invasion: a propensity score-matched analysis of multi-institutional cohort (2020)
  • Author(s): Matsunaga T,Komura K, Hashimoto T, Muraoka R,Satake N,Tsutsumi T,Tsujino T, Yoshikawa Y, Takai T,Minami K, Taniguchi K,Tanaka T, Uehara H,Hirano H,Nomi H, Ibuki N,Takahara K, Inamoto T,Ohno Y,Azuma H.
  • Journal Title: World Journal of Urology Volume: 38 Issue: 12 Pages: 3183-3190
  • DOI: 10.1007/s00345-020-03118-x
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Down-Grading of Ipsilateral Hydronephrosis by Neoadjuvant Chemotherapy Correlates with Favorable Oncological Outcomes in Patients Undergoing Radical Nephroureterectomy for Ureteral Carcinoma .. (2020)
  • Author(s): Miyake M,Marugami N, Fujiwara Y, Komura K,Inamoto T,Azuma H, Matsumoto H, Matsuyama H, Fujimoto K.
  • Journal Title: Diagnostics Volume: 10(1) Issue: 1 Pages: 10-10
  • DOI: 10.3390/diagnostics10010010
  • Peer Reviewed / Open Access
• [Journal Article] MicroRNA-143/Musashi-2/KRAS cascade contributes positively to carcinogenesis in human bladder cancer. (2019)
  • Author(s): Tsujino T,Sugito N, Taniguchi K, Honda R, Komura K, Yoshikawa Y, Takai T, Minami K, Kuranaga Y, Shinohara H, Tokumaru Y, Heishima K, Inamoto T, Azuma H, Akao Y.
  • Journal Title: Cancer Sci. Volume: 110(7) Issue: 7 Pages: 2189-9
  • DOI: 10.1111/cas.14035
  • Peer Reviewed / Open Access
• [Presentation] BU1B/BUBR1異常発現によるMutagenic NHEJとintact ATMの意義 (2020)
  • Author(s): 小村 和正,稲元 輝生,東 治人.
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] 放射線化学療法耐性尿路上皮がんにおけるError-Prone DNA Repairの異常亢進と臨床への意義. (2019)
  • Author(s): 小村和正、稲元輝生、東 治人。
  • Organizer: 第78回日本癌学会学術総会