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

Figures & data

Table 1 Differential Diagnoses of SMARCB1 Deficient (Pediatric) CNS Tumors

Tumor Grade	Tumor Type	Histopathology	Localization	Genomic Alterations	DNA Methylation Profile	Age at Diagnosis	Prognosis
Low	LGDIT, SMARCB1 mutant^Citation13	Low to moderate cellularity, pleomorphic glial and neuronal cells, Ki67 8%	Supratentorial	Homozygous SMARCB1-deletion	Similarity to ATRT-MYC	Median 16 years	Good response to multimodal treatment, but potential to progress to ATRT
Low	Desmoplastic myxoid tumor, SMARCB1-mutant^Citation15	Spindle and epithelioid cells embedded in a desmoplastic stroma, loose myxoid matrix; Ki67 3%	Pineal region	Heterozygous or homozygous SMARCB1 deletion	Distinct DNA methylation profile in proximity to ATRT-MYC	Median 40 years (15–61 years)	Stable disease without CT, RT following complete surgical resection
High	ATRT	Poorly differentiated, multi-lineage phenotype, glial, mesenchymal, epithelial components, rhabdoid cells, small round blue cells^Citation5,Citation20	Supratentorial, infratentorial and (less common) spinal^Citation4	Biallelic alterations in SMARCB1/ SMARCA4, GLM in 30%^Citation4,Citation21–23	ATRT TYR SHH MYC^Citation24	Median 18 months^Citation25	5-year OS 0–71% dependent on risk factors^Citation4
High	Cribriform neuroepithelial tumor (CRINET)^Citation16	Cribriform growth pattern with neuroepithelial tumor cells; Ki67/MIB1 30%,	Often intraventricular	Large heterozygous deletions of 22q + SMARCB1 mutations, often affecting the C-terminus^Citation26	Similarity with ATRT-TYR	10–26 months	Good response to multimodal treatment (1 partial resection, CT, RT; 1 GTR, CT)^Citation16
High	ATRT with molecular features of PXA^Citation18	Rhabdoid cells, brisk mitotic activity, geographic necroses, Ki67 high 15–60%	Supratentorial, temporal lobe	Homozygous SMARCB1 deletion, genetic features of PXA (homozygous CDKN2A/B deletion), gain of whole chromosome 7 BRAF V600E mutations)	Similarity with PXA	10–18 years, (1 case report of a 62-year old female)	To be determined, BRAF mutation as novel therapeutic target?
High	SMARCB1-deficient malignant brain tumors in the context of Li-Fraumeni syndrome^Citation19	Glial phenotype, pleomorphic nuclei, fibrillary process, no nuclear accumulation of p53 protein, scattered rhabdoid tumor cells^Citation4	Supratentorial, temporal lobe	Complex copy number alterations and TP53 mutation	Similarity with ATRT or malignant gliomas.	5–19 years	Depending on histopathological profile; to be determined

Table 2 Overview of the Results of Clinical Phase III Trials and Consensus Regimens Exclusively in ATRT

Phase	Title and Identifier	PI	Completion Date	Treatment		Results Published	Comments	Reference	Topic
III	Children’s Oncology Group Trial ACNS0333 (NCT00653068)	A. Reddy	August, 2023	Maximal safe tumor resection 2 cycles induction 3 cycles consolidation plus RT (sequence dependent on age and tumor localization) 4-year Follow up period		65 patients 4-year EFS 37% 4-year OS 43% < 36 months 4-year EFS 35% (improved compared to historical cohort) 3 toxic deaths ≥ 36 months 4-year EFS 48% 4-year OS 57% 1 toxic death 4-year OS 49% for “RT before consolidation” 4-year OS 48% for “consolidation before RT” 50% treatment failure (16/33 local failure)	Two treatment arms, but non-randomized Challenging cohort (83% younger than 36 months, 30% younger than 12 months, 37% with M+, 38% with GTR) Improved survival for patients younger than 36 months High amount of safety relevant toxicity No information on cognitive and psychological late effects	[45]	Radiotherapy and HDCT
II	Multi-institutional Phase II clinical trial to test efficacy or aggressive multimodality approach for children with newly diagnosed ATRT (DFCI)	S N Chi	May, 2008	Maximal safe tumor resection Modified IRS-III including intrathecal chemotherapy: Pre-RT chemotherapy Chemoradiation post-RT induction Maintenance therapy Continuation therapy	20 patients 2-year PFS 53% (± 13%) 2-year OS 70% (± 10%) 5-year OS 49.6% 10-year OS 44.7% Median survival 5.2 years 58% objective response to induction therapy 38% response to RT 8 long-time survivors (median FU 14.7 years; median 1.9 years at diagnosis, localized disease, RT, 6/8 with upfront GTR/STR) Succumbed (10): 5/10 M+, 7/10 with upfront biopsy/partial resection 40% refractory or recurrent disease (max 4 years of data reporting) 1 toxic death (pneumococcal sepsis)		Prospective multicenter trial, single arm, Beneficial cohort (Median age at diagnosis 26 months (60% younger than 36 months, 20% younger than 12 months), 30% with M+, 50% with GTR) Short follow up period Small cohort size	[56,59]	Radiotherapy, intrathecal chemotherapy
registry	The Canadian Paediatric Brain Tumor Consortium experience (CBTC)	L. Lafay-Cousin		Maximal safe tumor resection 10/50 in palliation 22/40 conventional chemotherapy (baby brain, IRS III like, ICE regimens, 9/22 anthracycline based) 18/40 HDCT (Head start, Triple Carboplatin/Thiotepa, MTX induction + Triple Carboplatin/Thiotepa) 9/40 intrathecal chemotherapy 21/40 radiation	50 patients Projected 2-year OS 36.4% ± 7.7 Median time of survival 13.5 months 75% with progress/relapse (median time to progression 5.5 months) Significant prognostic risk factors: GTR: 2-year OS (GTR) 60% ±12.6) 2-year OS (non GTR) 21.7% ± 8.5, p = 0.03 HDCT: 2-year OS (HDCT) 47.9% ±12.1 2-year OS (non HDCT) 27.3% ± 9.5, p= 0.036 Not-significant factors: Age: median survival time: 9.6 months in patients < 12 months 17.4 months in patients 12–36 months: 19.1 months in patients > 36 months: Upfront radiation no survival benefit! 6/12 survivors without radiation		Multicentric retrospective analysis Small cohort (n=50) Unfavorable cohort (median age at diagnosis 16.7 months, 76% younger than 36 months, 38% with M+, 30% with GTR, 2 synchronous MRT, 3 with diagnosed GLM) Best overall response not evaluated/not reported (radiographic CR, PR, SD etc) 75% refractory/ recurrent disease (max. 32 months) Multicenter Neuropsychological results in long-time survivors published three years later
Registry	EU-RHAB	M C. Frühwald	May, 2023	Maximal safe tumor resection Anthracycline based chemotherapy (9 to 12 courses) Age-dependent radiotherapy (no RT in < 18 months) HDCT (Carboplatin/Thiotepa + ASCT) on physician’s choice	143 patients 5-year OS 34.7 ± 4.5% 5-year EFS 30.5 ± 4.2% Median follow up 49.9 months 64% relapse or progression (mainly locally) 57% died due the time of analysis 3 cases of secondary malignancies (AML) No toxic death Independent significant prognostic factors: Age at diagnosis (< 1 year vs ≥ 1 year) DNA methylation subtype (TYR vs non-TYR) Dependent significant prognostic factors: Synchronous tumor (yes vs no) Metastases (M0 vs M+) Radiotherapy (yes vs no) Complete remission (yes vs. no) GLM (yes vs no)		Multicentric retrospective analysis Unfavorable cohort (median age at diagnosis 29.5 months, 86% younger than 36 months (35% younger than 12 months, 51% 12–35 months), 30% with M+, 34% with GTR) Large cohort Genetic and molecular information available	[4]

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.⁸⁶ 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.

Abbreviations: CTLA4, cytotoxic T-lymphocyte-associated protein 4; TCR, T cell receptor; MHC, major histocompatibility complex; PD-1, programmed death protein 1; PD-L1, programmed death ligand 1.

Table 3 Overview of Ongoing Clinical Trials Phases I and II Including Patients with ATRT

Inhibitor Group		Inhibitor	NCT Number	Phase	Study Completion
Immunotherapy	CAR T cells	B7-H3-specific	NCT04185038	I	2041
		C7R-GD2	NCT04099797	I	2039
		HER2-specific	NCT03500991	I	2039
		EGFR806-specific	NCT03638167	I	2040
	Immunovirus therapy	HSV G207	NCT03911388	I	2025
Immune-checkpoint inhibitors	PD-1/CTLA4-Inhibitors	Nivolumab + Ipilimumab + Tazemetostat	NCT05407441*	I/II	2029
	PD-1/CTLA4-Inhibitors	Nivolumab + Ipilimumab	NCT04416568*	II	2025
	PD-L1-Inhibitors	Atezolizumab + Tiragolumab	NCT05286801*	I/II	2025
	PD-1/HDI	Nivolumab + Entinostat	NCT03838042	I/II	2025
Cell cycle inhibitors	CDK4/6 inhibitor	Ribociclib + Gemcitabine Ribociclib + trametinib	NCT03434262	I	2025
		Ribociclib + TOTEM	NCT05429502	I/II	2028
		Abemaciclib (+RT)	NCT02644460	I	2024
		Abemaciclib (+ CTx)	NCT04238819	I/II	2028
		Palbociclib	NCT03709680**	I/II	2025
Targeted therapy	BRD9-degrader	FHD-609	NCT04965753**	I	2025
Targeted tumor cell radiotherapy	Phospholipid drug conjugate	CLR 131	NCT03478462	I	2024
	Radiolabeled monoclonal antibody	Iodine I131 MOAB 8H9	NCT00089245	I	2025
Protein kinase inhibitor	BCR-ABL tyrosine kinase inhibitor	Dasatinib	NCT00788125	I/II	June 20, 2023
	mTOR inhibitor	Sirolimus	NCT02574728	II	2024
	Aurora Kinase A inhibitor	Alisertib	NCT02114229*	II	2027
Replication	Folic acid analogue	Methotrexate	NCT02905110	Early Phase I	November 2023
Conventional therapy	Conventional chemotherapy, radiotherapy	Risk-adapted therapy	NCT00602667 (infants) NCT00085202 (children)	II	April 2026, December 2023
	HDCT/ASCT, radiotherapy	Controlled, randomized	EudraCT 2018-003335-29*	III	June 2029

Notes: *ATRT exclusive (including rhabdoid tumors, SMARCB1-deficient tumors); **SMARCB1-deficient tumors focusing on soft tissue tumors.

Abbreviations: AML, acute myeloid leukemia; ASCT, autologous stem cell transplantation; ATRT, atypical teratoid/rhabdoid tumor; CAR T cell, chimeric antigen receptor T cell; CD4T, CD4+ T cell; CDK, cyclin dependent kinase; cfDNA, cell free DNA; CNS, central nervous system; CNV, copy number variations; CRINET, cribriform neuroepithelial tumor; CSF, cerebrospinal fluid; CT, chemotherapy; ctDNA, circulating tumor DNA; CTLA4, cytotoxic T-lymphocyte associated protein 4; DFCI, Dana-Farber Cancer Institute; DIPG, diffuse intrinsic pontine glioma; DNA, desoxyribonucleic acid; DZNep, 3-Deazoplanocin; EED, embryonic ectoderm development; eMRT, extracranial, extrarenal malignant rhabdoid tumor; EU-RHAB, European Rhabdoid Registry; EZH2, enhancer of zeste homolog 2; FDA, Food and Drug Administration; GEMM, genetically engineered mouse model; GLM, germ line mutation; GTR, gross total resection; HDCT, high-dose chemotherapy; HDI, histone deacetylase inhibitor; INI1, integrase interactor 1; IVCT, intraventricular chemotherapy; LGDIT, low grade diffusely infiltrative tumor; M, metastatic; MDM2, murine double minute 2 homolog; MDS, myelodysplastic syndrome; MEK, mitogen-activated protein kinase kinase enzymes; MOAB, monoclonal antibody; MRD, minimal residual disease; MTX, methotrexate; MV-NIS, measles virus (MV) expressing human thyroidal sodium iodide symporter (NIS); oHSV, oncolytic herpes simplex virus; OS, overall survival; PARP, Poly (ADO-ribose) polymerase; PBT, proton beam therapy; PD-1, programmed death protein 1; PD-L1, programmed death ligand 1; PDOX, patient derived orthotopic xenograft; PFS, progression free survival; PR, partial remission; PRC2, polycomb repressive complex; PXA, pleomorphic xanthoastrocytoma; RB, retinoblastoma protein; r/r, recurrent or refractory; RT, radiotherapy; RTK, rhabdoid tumor of the kidney; RTPS, rhabdoid tumor predisposition syndrome; SD, stable disease; SMARCA4, SWI/SNF related matrix associated, actin dependent regulator of chromatin, subfamily a, member 4; SMARCB1, SWI/SNF related matrix associated, actin dependent regulator of chromatin, subfamily b, member 1; SWI/SNF, switch/sucrose non-fermentable; TME, tumor microenvironment; TMB, tumor mutational burden.

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.

Abbreviations: GLM, germ line mutation; GTR, gross total resection; M, metastasis; y, year of age at diagnosis.

Hasselblatt M, Thomas C, Federico A, et al. Low-grade diffusely infiltrative tumour (LGDIT), SMARCB1-mutant: a clinical and histopathological distinct entity showing epigenetic similarity with ATRT-MYC. Neuropathol Appl Neurobiol. 2022;48(4):e12797. doi:10.1111/nan.12797

 PubMed Web of Science ®Google Scholar

Thomas C, Wefers A, Bens S, et al. Desmoplastic myxoid tumor, SMARCB1-mutant: clinical, histopathological and molecular characterization of a pineal region tumor encountered in adolescents and adults. Acta Neuropathol. 2020;139(2):277–286. doi:10.1007/s00401-019-02094-w

 PubMed Web of Science ®Google Scholar

Oka H, Scheithauer BW. Clinicopathological characteristics of atypical teratoid/rhabdoid tumor. Neurol Med Chir. 1999;39(7):510–517; discussion 517–518. doi:10.2176/nmc.39.510

 Web of Science ®Google Scholar

Nesvick CL, Lafay-Cousin L, Raghunathan A, Bouffet E, Huang AA, Daniels DJ. Atypical teratoid rhabdoid tumor: molecular insights and translation to novel therapeutics. J Neurooncol. 2020;150(1):47–56. doi:10.1007/s11060-020-03639-w

 PubMed Web of Science ®Google Scholar

Frühwald MC, Hasselblatt M, Nemes K, et al. Age and DNA methylation subgroup as potential independent risk factors for treatment stratification in children with atypical teratoid/rhabdoid tumors. Neuro Oncol. 2020;22(7):1006–1017. doi:10.1093/neuonc/noz244

 PubMed Web of Science ®Google Scholar

Johann PD, Erkek S, Zapatka M, et al. Atypical teratoid/rhabdoid tumors are comprised of three epigenetic subgroups with distinct enhancer landscapes. Cancer Cell. 2016;29(3):379–393. doi:10.1016/j.ccell.2016.02.001

 PubMed Web of Science ®Google Scholar

Erdmann FKP, Grabow D, Spix C. German Childhood Cancer Registry Annual Report 2019 (1980–2018). Mainz: Institute of Medical Biostatistics, Epidemiology and informatics (IMBEI) at the University Medical Center of the Johannes Gutenberg University; 2020.

 Google Scholar

Hasselblatt M, Oyen F, Gesk S, et al. Cribriform neuroepithelial tumor (CRINET): a nonrhabdoid ventricular tumor with INI1 loss and relatively favorable prognosis. J Neuropathol Exp Neurol. 2009;68(12):1249–1255. doi:10.1097/NEN.0b013e3181c06a51

 PubMed Web of Science ®Google Scholar

Johann PD, Hovestadt V, Thomas C, et al. Cribriform neuroepithelial tumor: molecular characterization of a SMARCB1-deficient non-rhabdoid tumor with favorable long-term outcome. Brain Pathol. 2017;27(4):411–418. doi:10.1111/bpa.12413

 PubMed Web of Science ®Google Scholar

Thomas C, Federico A, Sill M, et al. Atypical Teratoid/Rhabdoid Tumor (AT/RT) with molecular features of pleomorphic xanthoastrocytoma. Am J Surg Pathol. 2021;45(9):1228–1234. doi:10.1097/PAS.0000000000001694

 PubMed Web of Science ®Google Scholar

Hasselblatt M, Thomas C, Federico A, et al. SMARCB1-deficient and SMARCA4-deficient malignant brain tumors with complex copy number alterations and TP53 mutations may represent the first clinical manifestation of li-fraumeni syndrome. Am J Surg Pathol. 2022;46(9):1277–1283. doi:10.1097/PAS.0000000000001905

 PubMed Web of Science ®Google Scholar

Reddy AT, Strother DR, Judkins AR, et al. Efficacy of high-dose chemotherapy and three-dimensional conformal radiation for atypical teratoid/rhabdoid tumor: a report from the Children’s Oncology Group Trial ACNS0333. J Clin Oncol. 2020;38(11):1175–1185. doi:10.1200/JCO.19.01776

 PubMed Web of Science ®Google Scholar

Chi SN, Zimmerman MA, Yao X, et al. Intensive multimodality treatment for children with newly diagnosed CNS atypical teratoid rhabdoid tumor. J Clin Oncol. 2009;27(3):385–389. doi:10.1200/JCO.2008.18.7724

 PubMed Web of Science ®Google Scholar

Gonzalez G, Delgado M, Blanco A, Puentes M. SIOP ABSTRACTS. Pediatr Blood Cancer. 2021;68(Suppl 5):e29349. doi:10.1002/pbc.29349

 PubMedGoogle Scholar

Matthews HK, Bertoli C, de Bruin RAM. Cell cycle control in cancer. Nat Rev Mol Cell Biol. 2022;23(1):74–88. doi:10.1038/s41580-021-00404-3

 PubMed Web of Science ®Google Scholar