Developing novel therapeutics for Translocation Renal Cell Carcinoma by sequence specific DNA alkylation

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K19619
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 56:Surgery related to the biological and sensory functions and related fields
• Research Institution: Kumamoto University
• Principal Investigator: Baba Masaya 熊本大学, 国際先端医学研究機構, 准教授 (10347304)
• Co-Investigator(Kenkyū-buntansha): 杉山 弘 京都大学, 理学研究科, 教授 (50183843) ; 上久保 靖彦 京都大学, 医学研究科, 特定教授 (60548527)
• Project Period (FY): 2018-06-29 – 2020-03-31
• Keywords: 転座腎細胞癌 / 融合転写因子 / TFE3 / 抗がん剤 / 創薬

Outline of Final Research Achievements

Chromosomal translocation derived fusion TFE3 drives genome wide aberrant transcription and causes Translocation Renal Cell Carcinoma (tRCC). In this research project, our goal was to develop a novel anti-cancer drug, which blocked fusion TFE3 target genes’ transcription by alkylating DNA containing fusion TFE3 recognition motifs. We evaluated the candidate drugs by measuring the inhibitory effect on fusion TFE3 target genes’ expression and selected the most promising candidate drug. The tRCC cell lines, which were treated with this candidate drug, demonstrated G2/M arrest followed by senescence and growth inhibition in a dose dependent manner.

Free Research Field

医化学

Academic Significance and Societal Importance of the Research Achievements

転写因子を標的とした創薬はこれまで困難を極めて来た。本研究では、がんの原因となる異常な融合TFE3転写因子自体では無く、融合TFE3が結合する塩基配列を標的とするというこれまでに無い戦略をとり、薬剤の開発に挑んだ。その結果融合TFE3の転写標的遺伝子の発現を抑え、融合TFE3を発現している腎細胞がんの増殖を用量依存的に抑制する有望な薬剤候補分子を得ることができた。今後、異常な転写をゲノムワイドにブロックする画期的ながん治療薬開発への展開が期待される。