Academic Paper Presentation – Professor Che-Chang Chang & Student Le Hien Giang

Targeting of RRM2 suppresses DNA damage response and activates apoptosis in atypical teratoid rhabdoid tumor

Atypical teratoid rhabdoid tumor (ATRT) stands out as the most prevalent central nervous system tumor among infants under the age of one. Despite its high incidence, a standardized treatment protocol for ATRT is yet to be established. Prognosis generally remains unfavorable, with survival rates varying based on age and treatment. Consequently, there is an urgent imperative to identify an effective treatment for this cancer.

Addressing this critical need, Professor Che-Chang Chang and his colleagues at TMU recently published groundbreaking research in the Journal of Experimental and Clinical Cancer Research (Giang et al., J Exp Clin Cancer Res (2023) 42:346). Their study delves into RRM2, a subunit of

ribonucleotide reductase, which exhibits elevated expression in ATRT tumors when compared to benign or normal brain tissues, correlating with a poor prognosis. Silencing RRM2 has demonstrated inhibitory effects on cell proliferation, migration, and colony formation. Remarkably similar outcomes were observed with the RRM2 inhibitor COH29, currently undergoing clinical trials for solid tumors.

The impact of COH29 has been comprehensively examined using RNAseq and validated by cellular functional assays and Western blot analysis. Mechanistically, inhibition of RRM2 induces DNA damage and blocks the expression of DNA repair genes, ultimately leading to apoptosis in ATRT cells. The authors provide compelling evidence for the downregulation of pivotal genes involved in homologous recombination (HR), including BRCA1 and RAD51, and activation of the apoptotic pathway. Furthermore, an orthotopic model of ATRT treated with COH29 showed a significant reduction in tumor growth along with prolonged overall survival.

The findings of their study substantiate RRM2 as a viable druggable target, as evidenced by experiments using shRNA and the molecular target drug COH29 in vitro and in vivo. These results provide strong support for the feasibility of clinical trials, especially for ATRT patients who currently lack viable treatment options. The demonstrated efficacy of interventions targeting RRM2 suggests a promising avenue for the development of novel treatments and brings hope to individuals facing limited therapeutic alternatives in the context of ATRT.