Clinical evidence for a biological effect of epigenetically active decitabine in relapsed or progressive rhabdoid tumors

Steinbügl, Mona; Nemes, Karolina; Johann, Pascal; Kröncke, Thomas; Tüchert, Stefanie; Costa, Maria Joao Gil da; Ebinger, Martin; Schüller, Ulrich; Sehested, Astrid; Hauser, Péter; Reinhard, Harald; Sumerauer, David; Hettmer, Simone; Jakob, Marcus; Hasselblatt, Martin; Siebert, Reiner; Witt, Olaf; Gerß, Joachim; Kerl, Kornelius; Frühwald, Michael C.

doi:10.1002/pbc.29267

Cited by 8 publications

(6 citation statements)

References 71 publications

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“…Based on our results, the temporal relationship to the DNA demethylation might be one of the key determinants of the cell fate after SMARCB1 inactivation. This is supported by recent findings that AT/RTs respond well to DNA methyltransferase inhibition both in vitro and in vivo ( Steinbügl et al, 2021 ; Graf et al, 2022 ). Further research will show if this or similar therapeutic approaches could benefit patients suffering from this devastating disease.…”

Section: Discussionsupporting

confidence: 82%

Aberrant DNA methylation distorts developmental trajectories in atypical teratoid/rhabdoid tumors

Pekkarinen,

Nordfors,

Uusi-Mäkelä

et al. 2024

Life Sci. Alliance

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Atypical teratoid/rhabdoid tumors (AT/RTs) are pediatric brain tumors known for their aggressiveness and aberrant but still unresolved epigenetic regulation. To better understand their malignancy, we investigated how AT/RT-specific DNA hypermethylation was associated with gene expression and altered transcription factor binding and how it is linked to upstream regulation. Medulloblastomas, choroid plexus tumors, pluripotent stem cells, and fetal brain were used as references. A part of the genomic regions, which were hypermethylated in AT/RTs similarly as in pluripotent stem cells and demethylated in the fetal brain, were targeted by neural transcriptional regulators. AT/RT-unique DNA hypermethylation was associated with polycomb repressive complex 2 and linked to suppressed genes with a role in neural development and tumorigenesis. Activity of the several NEUROG/NEUROD pioneer factors, which are unable to bind to methylated DNA, was compromised via the suppressed expression or DNA hypermethylation of their target sites, which was also experimentally validated for NEUROD1 in medulloblastomas and AT/RT samples. These results highlight and characterize the role of DNA hypermethylation in AT/RT malignancy and halted neural cell differentiation.

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Section: Discussionsupporting

confidence: 82%

Aberrant DNA methylation distorts developmental trajectories in atypical teratoid/rhabdoid tumors

Pekkarinen,

Nordfors,

Uusi-Mäkelä

et al. 2024

Life Sci. Alliance

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“…In addition, among 99 RT patients from the EU-RHAB median overall survival after relapse and progression was 18 weeks, and only 20% were alive one year after relapse and progression. [8].…”

Section: Discussionmentioning

confidence: 99%

Effective treatment of recurrent orbital Rhabdoid Tumor with Predisposition Syndrome 1

Abrishami

Maurer

Stüben

et al. 2022

Preprint

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Rhabdoid tumor with predisposition syndrome 1 is a highly aggressive, rare genetic condition in young children. We report an 18-month-old child with bleeding from a second local recurrence of an orbital rhabdoid tumor. Due to the rarity of the syndrome there are no generally accepted treatment approaches, especially in tumor recurrences. As a rescue therapy, our patient received a combination of transarterial embolization and interstitial brachytherapy (BT). From the initiation of our treatment until his death, he experienced neither recurrent bleeding nor local tumor recurrence. The combination of embolization and BT might offer a safe palliative approach and could be considered as a possible alternative at an earlier stage.

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“…Retrospective analyses of decitabine in 22 patients with r/r rhabdoid tumors reported radiologic responses in 27% (total n=6, 4= ATRT). 85 Complete remission was achieved in one patient, who received further conventional chemotherapy, while in most patients, response was detected in isolated foci, only. As radiographic response was associated with prolonged time to progression and overall survival, 85 decitabine deserves further evaluation, eg, as bridging therapy in patients with r/r disease.…”

Section: Potential Targeted Therapeutic Approaches To Atrtmentioning

confidence: 95%

“…IVCT) but also radiotherapy modalities, as well as smart combination elements. 85 The concept of future clinical trials depends on international (drug) availability and the capacity to recruit suitable cohorts. The fortunately increasing number of long-time survivors highlights the need to attend to and study the physical and mental development as well as aspects of quality of life in survivors.…”

Section: Clinical Management Of Atypical Teratoid Rhabdoid Tumors – C...mentioning

confidence: 99%

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

Gastberger,

Fincke,

Mucha

et al. 2023

CMAR

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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.

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Clinical evidence for a biological effect of epigenetically active decitabine in relapsed or progressive rhabdoid tumors

Abstract: Background: Refined therapy has helped to improve survival rates in rhabdoid tumors (RT). Prognosis for patients with chemoresistant, recurrent, or progressive RT remains dismal. Although decitabine, an epigenetically active agent, has mainly been evaluated

Cited by 8 publications

References 71 publications

Aberrant DNA methylation distorts developmental trajectories in atypical teratoid/rhabdoid tumors

Aberrant DNA methylation distorts developmental trajectories in atypical teratoid/rhabdoid tumors

Effective treatment of recurrent orbital Rhabdoid Tumor with Predisposition Syndrome 1

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

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