Current Molecular and Clinical Landscape of ATRT - The Link to Future Therapies

Abstract

ATRT is a highly aggressive and rare pediatric CNS tumor of very young children. Its genetic hallmark is bi-allelic inactivation of SMARCB1 encoding INI1. Rarely SMARCA4 encoding BRG1 is affected. Up to 30% are associated with constitutional heterozygous pathogenic variants in one of the two genes, giving rise to the Rhabdoid-Tumor-Predisposition-Syndromes (RTPS) 1 and 2. Characteristic DNA methylation profiles distinguish ATRT from other SMARCB1-deficient entities. Three distinct subtypes ATRT-MYC, -TYR, and -SHH are on record. ATRT-SHH may be further divided into the subgroups ATRT-SHH1A, -SHH1B, and -SHH2. The cure of ATRT remains challenging, notwithstanding an increasing understanding of molecular pathomechanisms and genetic background. The implementation of multimodal institutional treatment protocols has improved prognosis. Regardless of treatment approaches, clinical risk factors such as age, metastases, and DNA methylation subtype affect survival probability. We provide a critical appraisal of current conventional multimodal regimens and emerging targeted treatment approaches investigated in clinical trials and entity-specific registries. Intense treatment approaches featuring radiotherapy (RT) and high-dose chemotherapy (HDCT) face the difficulty of balancing tumor control and treatment-related toxicity. Current approaches focus on minimizing radiation fields by proton beam therapy or to withhold RT in HDCT-only approaches. Still, a 40-75% relapse rate upon first-line treatment reveals the need for novel treatment strategies in primary and even more in recurrent/refractory (r/r) disease. Among targeted treatments, immune checkpoint inhibitors and epigenetically active agents appear most promising. Success remains limited in single agent approaches. We hypothesize that mechanism-informed combination therapy will enhance response, as the low mutational burden of ATRT may contribute to acquiring resistance to single targeted agents. As DNA methylation group-specific gene expression profiles appear to influence response to distinct agents, the future treatment of ATRT should respect clinical and biological heterogeneity in risk group adjusted treatment protocols.

Keywords: ATRT; CNS; SMARCB1; SWI/SNF related matrix associated; actin dependent regulator of chromatin; atypical teratoid rhabdoid tumor; cell cycle; central nervous system; member 1; pediatric; subfamily b; treatment.

Figure 1

Novel agents for ATRT therapy in clinical phase I and II trials - correlation to the tumor cell cycle. Arrows with even tips indicate “inhibition”, arrows with sharp tips indicate “activation”, fading arrows with sharp tips indicate “cell cycle exit into G₀ phase”. Therapeutic approaches located in the center and surrounded by the grey circle affect more than one distinct phase of the cell cycle in the form of modified gene repression by epigenetically active drugs (decitabine (DNA-hypomethylation), tazemetostat (H3K27me3), entinostat and panobinostat (HDACI)), or DNA damage dependent cell cycle exit in G₁ and G₂ (radiotherapy induced double strand breaks). *Reaching and passing decision windows is driven by appropriate cyclin/CDK levels: G₁/S transition is regulated by Cyclin D/CDK2/4/6, while Cyclin A/B/CDK1/2 affect G₂/M transition. A mitotic entry commitment point, a mitotic exit commitment point, or a S phase entry commitment point regulated by DNA damage, DNA replication stress, or spindle assessment are not shown in this figure. Created with Biorender.com.

Figure 2

Novel targets affecting the interaction between ATRT tumor cells and the immune system. Structures investigated in clinical phase I and II trials targeting the interaction of T and ATRT tumor cells. Current clinical trials are provided for each agent in form of the NCT identifier. Trials including SMARCB1/SMARCA4-deficient entities only (focus on ATRT) are highlighted with *. Arrows with even tips indicate “inhibition”, arrows with sharp tips “uptake in”. Created with Biorender.com.

Figure 3

Risk factor-based model for treatment decision in ATRT. For standard risk patients, multimodal conventional therapy is the first line choice. Patients not achieving an objective response (SD, stable disease) and non-responders (PD, progressive disease) will be re-stratified into an intermediate risk group. Treatment of intermediate risk patients may add individual or combined novel targeting agents to conventional therapy. Delayed (SD) and non-responders (PD) will drop to a high-risk stratum. Treatment in the high-risk stratum will be individualized based on genetic and molecular profiling, and/or patients will be included in phase I/II clinical basket trials. Black characters represent responders, grey characters non-responders to current or previous treatment. Exemplary risk factors are provided for potential stratification and have to be defined by further research in form of international meta-analysis. Created with Biorender.com.