Atypical Teratoid Rhabdiod Tumor (ATRT) is a pediatric central nervous system tumor. ATRT accounts for about 2% of pediatric CNS tumors, however it accounts for 20% of CNS tumors in children less than 3 years old (1). Overall survival for patients diagnosed with ATRT is a dismal 10-17 months, and 2 year survival for these patients in spite of continuing efforts and therapy remains at less than 20% (1, 2, 3, 4). Genomic profiling has suggested molecular differences within ATRT, and three genomic subtypes have been described; Group1-TYR, Group2A-SHH and Group2B-MYC (5). However, studies investigating ATRT have utilized a limited number of cell lines which do not fully represent the complex heterogeneity of this disease. Better understanding of this complex disease and developing novel treatment approaches are desperately needed.
What are the goals of this project?
The first aim of this project is to determine if pharmacological treatment of ATRT cell lines with DFMO results in reductions in viability, tumor initiation, and LIN28 protein levels. We will test a series of doses of DFMO to assess the effects on ATRT cell viability, proliferation rates, tumor initiation, and proteins of interest including LIN28.
The second aim of this project is to ascertain if DFMO induced effects in ATRT are pan disease or subtype specific. We will use a collection of ATRT cell lines with disparate molecular phenotypes and subgrouping to determine if treatment with DFMO produces similar results within a heterogeneous group of samples.
What is the impact of this project?
Improving outcomes for ATRT patients requires a better understanding of the disease and novel therapy development. These studies will provide a greater understanding of the role of LIN28 in ATRT and put that understanding in a subtype specific context. In addition, pharmacological targeting of LIN28 with DFMO will be employed providing an avenue for the development of an innovative treatment approach for this devastating disease. Information learned from these experiments may lead to the identification of biomarkers predictive of response to DFMO treatment and the development of clinical trials testing the efficacy of DFMO in ATRT patients.
Why is the CBTN request important to this project?
ATRT is a heterogenous disease comprised of multiple subtypes. Our current in vitro work with ATRT has utilized the ATCC provided cell line CHLA-02-ATRT. Without testing our hypothesis in a larger cohort of cell lines, more fully representing the heterogeneity within the disease, any conclusions that can be drawn based on our experiments are severely limited. Utilizing the resources generously available from CBTN will greatly improve the impact of the experiments we intend to complete.
The Children's Brain Tumor Network will contribute to this project by providing ATRT cell lines.
Atypical Teratoid/Rhabdoid Tumor
Central nervous system (CNS) atypical teratoid/rhabdoid tumor (AT/RT) is a very rare, fast-growing tumor of the brain and spinal cord. It usually occurs in children aged three years and younger, although it can occur in older children and adults. About half of these tumors form in the cerebellum or