A developmental research for a novel MDM4-targeted anti-cancer therapy

• Project/Area Number: 15K19160
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Applied pharmacology
• Research Institution: University of Tsukuba
• Principal Investigator: Yamamoto Yoshiyuki 筑波大学, 附属病院, 病院講師 (00649288)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: MDM4 / MDM2 / siRNA / dsRDC / p53 / Trametinib / KRAS変異 / ETS / RAS変異 / BRAF変異

Outline of Final Research Achievements

In TP53 wild-type tumors, MDM4 and MDM2 promote tumor progression by not only down-regulation of p53 but also interactions with molecular of MAPK pathway. In this study, we aim to evaluate the combination effects of double-stranded RNA-DNA chimera (dsRDC)-modified siRNAs targeting MDM4 and MDM2, and MEK inhibitor (Trametinib). At first, the combination of these 3 drugs showed the potent synergistic effects on MDM4 overexpressed TP53 wild-type, and RAS mutant cancer cell lines. In addition, this triple-drug combination induced apoptosis and cell cycle arrests (G1 and G2 arrests). Further studies are needed to reveal the mechanism of this synergistic effect.