Cancer research and therapy in ATRT

ATRTs are among the most malignant brain tumors in early childhood and remain incurable. 

(1) We performed DGE and GSEA analysis on matched primary and recurrent PDX samples from an infant with ATRT to find a proteasome component as a drug target. BTZ inhibited tumor growth and prolonged survival in Myc-ATRT orthotopic xenograft mice. Our findings suggest that BTZ may be a promising targeted therapy for Myc-ATRTs. We achieved using BTZ as an add-on therapy to standard and HDC for ATRTs in children for a clinical Phase II investigator-initiated trial (ECRC補助IIT案-1091-18).  Cancers  2020, 12:752. 

(2) Ribonucleotide reductase regulatory subunit M2 (RRM2) is the building subunit of the ribonucleotide reductase enzyme that is important for DNA synthesis and repair. The vital roles of RRM2 in controlling the progression of many cancers have been reported.  We found that RRM2 was highly expressed in multiple independent ATRT clinical cohorts. Additionally, the expression level of RRM2 was significantly associated with poor survival outcomes. Depletion of RRM2 by the shRNA strategy or RRM2 inhibitor treatment significantly inhibited cell viability, colony formation, and migration. Furthermore, inhibition of RRM2 expression led to activation of DNA damage and induced cell apoptosis. Together, our data suggest that RRM2 is associated with the progression of ATRT and may be a potential therapeutic target for this tumor. J Exp Clin Cancer Res 2023, 42:346.

This intern project aims to comprehensively evaluate the role of RRM2 as a molecular radiosensitizer in ATRT using 2D and 3D cell culture models. Functional assays, including apoptosis, proliferation, cell cycle, and clonogenic assays, will be employed to assess the synergistic effects of RRM2 inhibitors in radiation treatment. Additionally, we will explore the regulatory mechanisms of COH29 under varying doses of radiation exposure. Immunohistochemistry on the spheroid will determine the expression of proteins related to cellular function.
Building on our established pediatric ATRT research framework, this project seeks to identify targets for reduced-dose radiotherapy. By elucidating the role of RRM2 under radiation, we aim to develop effective combination therapies for ATRT. The findings could pave the way for multicenter collaborations and clinical trials, offering therapeutic strategies that minimize neurocognitive impairments and improve the quality of life for young patients.