Development of anticancer drugs based on a new oncogenic mechanism of a novel oncogene candidate molecule TRB1

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07052
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Nagoya City University
• Principal Investigator: Hayashi Hidetoshi 名古屋市立大学, 医薬学総合研究院(薬学), 教授 (80198853)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: TRB1 / c-Myc / CD44 / ROS / MAX / フェロトーシス / 遺伝子増幅 / がん幹細胞

Outline of Final Research Achievements

TRB1, which is located near the representative oncogene c-Myc on chromosomes and is highly expressed in many cancers, positively and negatively enhanced the transcriptional response of c-Myc and regulated the expression of its target genes. In the case of positive regulation, this is presumably because TRB1 increases the binding of c-Myc to its partner molecule MAX. Close crosstalk was also observed, with TRB1 and c-Myc positively regulating the expression of c-Myc and TRB1, respectively.
It was suggested that TRB1 is required for sphere-forming ability and contributes to the maintenance of cancer stem cell survival by stabilizing xCT and enhancing ROS scavenging ability and acquiring ferotosis resistance based on the increased expression of the cancer stem cell marker CD44v8-v10.

Free Research Field

生物系薬学

Academic Significance and Societal Importance of the Research Achievements

本研究ではc-Mycとのポジティブループのパートナー、がん幹細胞の生存維持作用など、TRB1の新たながん遺伝子としての一端が明らかとなった。c-Mycは多くのがんで高発現し、がんの発生や悪性化に大きく寄与することから、有望な治療標的として期待されてきたが、適切なdruggableな構造モチーフがなく、c-Mycを直接標的とする戦略は難航している。今回明らかにしたTRB1-c-MycのポジティブループのTRB1を標的とすれば、c-Mycの機能を強く低減するとともに、がん細胞死を誘導し、まだ有効なc-Mycやがん幹細胞に対する治療薬のない現在、新たな創薬の標的として有望となると考えられる。