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:

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

Acknowledgments

We thank P. Neumayer and S. Breitmoser-Greiner for expert assistance. This publication was supported by ERN Paed Can.

Disclosure

MCF is supported by the “Deutsche Kinderkrebsstiftung” DKS 2010.03, the “Deutsche Forschungsgemeinschaft” DFGR FR 1516/4-1, the DKH 70113981, and the parent organization Lichtblicke.

RS received grant support by the Deutsche Krebshilfe 70114040, grants from Kinderkrebsinitiative Buchholz/Holm-Seppensen, the insurance pay for diagnostics but payment goes to my employer, during the conduct of the study; personal fees from Astra Zeneca, outside the submitted work;

MH’s research is supported by the DFG (HA 3060/8-1) and the IZKF Münster (Ha3/017/20).

VF receives a scholarship from the Konrad Adenauer Foundation.

KG reports grants from Deutsche Kinderkrebsstiftung (DKKS), during the conduct of the study.

The authors report no other conflicts of interest in this work.