Recent progress and novel approaches to treating atypical teratoid rhabdoid tumor.
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ABSTRACT:
SUBMITTER: Alva E
PROVIDER: S-EPMC9929860 | biostudies-literature | 2023 Mar
REPOSITORIES: biostudies-literature
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Recent progress and novel approaches to treating atypical teratoid rhabdoid tumor.
Alva Elizabeth E Rubens Jeffrey J Chi Susan S Rosenberg Tom T Reddy Alyssa A Raabe Eric H EH Margol Ashley A
Neoplasia (New York, N.Y.) 20230209
Atypical teratoid rhabdoid tumors (AT/RT) are malignant central nervous system (CNS) tumors that occur mostly in young children and have historically carried a very poor prognosis. While recent clinical trial results show that this tumor is curable, outcomes are still poor compared to other central nervous system embryonal tumors. We here review prior AT/RT clinical trials and highlight promising pre-clinical results that may inform novel clinical approaches to this aggressive cancer. ...[more]
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Project description:Atypical teratoid/rhabdoid tumor (AT/RT) is a rare CNS cancer that typically occurs in children younger than 3 years of age. Histologically, AT/RTs are embryonal tumors that contain a rhabdoid component as well as areas with primitive neuroectodermal, mesenchymal, and epithelial features. Compared to other CNS tumors of childhood, AT/RTs are characterized by their rapid growth, short symptomatic prodrome, and large size upon presentation, often leading to brain compression and intracranial hypertension requiring urgent intervention. For decades, the mainstay of care has been a combination of maximal safe surgical resection followed by adjuvant chemotherapy and radiotherapy. Despite advances in each of these modalities, the relative paucity of data on these tumors, their inherently aggressive course, and a lack of molecular data have limited advances in treatment over the past 3 decades. Recent large-scale, multicenter interdisciplinary studies, however, have significantly advanced our understanding of the molecular pathogenesis of these tumors. Multiple clinical trials testing molecularly targeted therapies are underway, offering hope for patients with AT/RT and their families.
| S-EPMC6656328 | biostudies-literature
Project description:IntroductionAtypical teratoid rhabdoid tumor (ATRT) is a rare, often lethal brain tumor of childhood characterized by a complex epigenetic landscape amongst a simple genetic background. Recent molecular studies have defined key biologic events that contribute to tumorigenesis and molecular subtypes of ATRT.MethodsSeminal studies on ATRT are reviewed with an emphasis on molecular pathogenesis and its relevance to novel therapeutics.ResultsIn this review, we summarize the key clinicopathologic and molecular features of ATRT, completed and ongoing clinical trials and outline the translational potential of novel insights into the molecular pathogenesis of this tumor.ConclusionsSMARCB1 loss is the key genetic event in ATRT pathogenesis that leads to widespread epigenetic dysregulation and loss of lineage-specific enhancers. Current work is defining subtype-specific treatments that target underlying molecular derangements that drive tumorigenesis.
| S-EPMC8230985 | biostudies-literature
Project description:BACKGROUND: To describe therapeutic approaches in children with atypical Teratoid Rhabdoid Tumours (ATRT) in France. METHODS: Observational study including all children less than 18 years old diagnosed with ATRT in France between 2009 and 2011. RESULTS: Forty seven children were included in this retrospective study. Six patients received no curative treatment while forty-one patients had a curative project. Median age was 1.5 years (range 0-16). The disease was disseminated in 10 patients. Surgical resection was complete in 21 cases. Chemotherapy was administered in 41 children. Twenty-six patients received upfront Vincristine-Methotrexate (5g/m2 x 3) with intra-thecal Methotrexate, which was stopped in eleven patients: in four cases the disease progressed and in seven cases the toxicities were manageable. Fifteen children received different chemotherapy courses and in four of them the diseases progressed. Eight patients underwent second-look surgery. Radiotherapy was administered in 17 patients at a median time of 19 weeks (13-44) after diagnosis. High-dose chemotherapy (HDCT) was given in 9 children and maintenance therapy in 5 children, starting at respectively 35 and 42 weeks after diagnosis. Median follow-up was 26 months (0.6-47). Median time for progression was 5 months. Two-years overall survival was 32% + /-8%. Median survival was 8 months. DISCUSSION: The survival rate of children with ATRT remains poor, the addition of VM is easily manageable but its benefit remains uncertain. The disease progressed mostly before radiotherapy. Future trials should focus on the delay of radiotherapy and the benefit of HDCT. Because ATRT is a rare disease of infancy carrying grim prognosis, focus on long term outcome, especially neurocognitive remain very limited. With the new era of multimodality therapy, some patients are now long term survivors. We reviewed the neuropsychological (NP) status of the survivors from the Canadian ATRT registry. Among patients diagnosed between 1995-2012, 16/72 were survivors (22%). Formal NP assessments were available in 7 patients. Four patients could not be tested (3 too young, 1 blind significantly impaired, 1 lost to follow up). Additionally 1 patient was in special education class (grade 12), one received educational assistance (grade 8), one meet academic expectation (grade 4). Data on last survivor is pending. For the 7 patients with comprehensive NP, the median age at diagnosis was 28.2 months (11.2-60.7). Four tumors were infratentorial and 3 were metastatic. Four patients underwent complete resection. All patients received post operative sequential high dose chemotherapy (Carpoplatin/Thiotepa). Five patients received intrathecal chemotherapy. Two patients underwent radiation (1focal, 1CSI). Median age at time of NP was 7.3 years (3.9-9.28). Full Scale Intellectual Quotient (FSIQ) ranged from 60 to 119 (median = 71). Simple expressive and receptive language appeared relatively preserved (low average to superior). Three most recently diagnosed patients assessed at a median time of 2.6 years (2.6-4.7) from diagnosis had average to high average scores for FSIQ, academic and visual spatial skills, visual and verbal memory. Four other diagnosed earlier tested at a median time of 5.1 years (3.3-8.3) post-diagnosis had a FSIQ ranging from 60 to 71 (median = 68). Approximately 50% of their scores were in the impaired range. Whether these findings suggest further decline overtime or reflect improvement in overall management of these recently diagnosed patients remain unclear. Nevertheless this cohort of infants appears significantly impaired at school age despite the absence of systematic radiotherapy. Larger series focusing on neurocognition are definitely needed before embracing adjuvant radiotherapy as standard of care.
| S-EPMC4046281 | biostudies-literature
Project description:Atypical teratoid rhabdoid tumor (ATRT) is a rare, highly malignant central nervous system cancer arising in infants and younger children, historically considered to be homogeneous, monogenic, and incurable. Recent use of intensified therapies has modestly improved survival for ATRT; however, a majority of patients will still succumb to their disease. While ATRTs almost universally exhibit loss of SMARCB1 (BAF47/INI1/SNF5), recent whole genome, transcriptome, and epigenomic analyses of large cohorts reveal previously underappreciated molecular heterogeneity. These discoveries provide novel insights into how SMARCB1 loss drives oncogenesis and confer specific therapeutic vulnerabilities, raising exciting prospects for molecularly stratified treatment for patients with ATRT.
| S-EPMC7339881 | biostudies-literature
Project description:BackgroundAtypical teratoid/rhabdoid tumor (AT/RT) is one of the most common malignant brain tumors in infants. Although cancer stem cells of AT/RT express aldehyde dehydrogenase (ALDH), effective chemotherapies against AT/RT have not been established. Here, we examined radiosensitizing effects of disulfiram (DSF), an irreversible inhibitor of ALDH against AT/RT for a novel therapeutic method.MethodsPatient-derived primary cultured AT/RT cells (SNU.AT/RT-5 and SNU.AT/RT-6) and established AT/RT cell lines (BT-12 and BT-16) were used to assess therapeutic effects of combining DSF with radiation treatment (RT). Survival fraction by clonogenic assay, protein expression, immunofluorescence, and autophagy analysis were evaluated in vitro. Antitumor effects of combining DSF with RT were verified by bioluminescence imaging, tumor volume, and survival analysis in vivo.ResultsThe results demonstrated that DSF at low concentration enhanced the radiosensitivity of AT/RT cells with reduction of survival fraction to 1.21‒1.58. DSF increased DNA double-strand break (γ-H2AX, p-DNA-PKcs, and p-ATM), apoptosis (cleaved caspase-3), autophagy (LC3B), and cell cycle arrest (p21) in irradiated AT/RT cells, while it decreased anti-apoptosis (nuclear factor-kappaB, Survivin, and B-cell lymphoma 2 [Bcl2]). In vivo, DSF and RT combined treatment significantly reduced tumor volumes and prolonged the survival of AT/RT mouse models compared with single treatments. The combined treatment also increased γ-H2AX, cleaved caspase-3, and LC3B expression and decreased ALDH1, Survivin, and Bcl2 expression in vivo.ConclusionsDSF and RT combination therapy has additive therapeutic effects on AT/RT by potentiating programmed cell death, including apoptosis and autophagy of AT/RT cells. We suggest that DSF can be applied as a radiosensitizer in AT/RT treatment.
| S-EPMC5570172 | biostudies-literature
Project description:Background: Atypical teratoid/rhabdoid tumor in adults is a relatively rare malignant neoplasm. It is characterized by the presence of rhabdoid cells in combination with loss of either the INI1 or BRG1protein from the tumor cells. Methods: A systematic review was conducted using MEDLINE using the terms "atypical teratoid rhabdoid tumor" AND "adult." The systematic review was supplemented with relevant articles from the references. Cases were included if the pathology was confirmed by loss of INI1 or BRG1. We included a case from our institution. The dataset was analyzed using descriptive statistics and log-rank test. Results: A total of 50 cases from 29 articles were included in this study. The average age at diagnosis was 36.7 years. The most common locations reported are the sellar region and cerebral hemispheres (without deep gray matter involvement). Of the 50 cases, 14 were reported to show evidence of dissemination. The average overall survival was 20 months. There was a significant difference in survival between the adjuvant therapy groups (p = < 0.0001). Conclusion: Atypical teratoid rhabdoid tumor of the central nervous system in adults is a rare neoplasm associated with a poor prognosis in a majority of patients. The treatment and clinical course are highly variable, and it remains unclear which factors impact prognosis.
| S-EPMC6279935 | biostudies-literature
Project description:Atypical teratoid rhabdoid tumors (AT/RTs) are rare pediatric brain tumors characterized by bialleic loss of the SMARCB1 tumor suppressor gene. In contrast to pediatric AT/RT that has a simple genome, very little is known about the adult AT/RT genomic landscape. Using a combination of whole-exome sequencing and high-resolution SNP array in a single adult pituitary AT/RT, we identified a total of 47 non-synonymous mutations, of which 20 were predicted to cause non-conservative amino acid substitutions, in addition to a subclone of cells with trisomy 8. We suggest that adult AT/RT may not be markedly dissimilar to other adult brain tumors where mutations in a range of genes, reflecting the functional specialization of different brain regions, but including SMARCB1 inactivation, may be required for its pathogenesis.
| S-EPMC4617150 | biostudies-literature
Project description:Atypical teratoid rhabdoid tumors (ATRT) are rare and aggressive embryonal tumors of central nervous system that typically affect children younger than 3 years of age. Given the generally poor outcomes of patients with ATRT and the significant toxicities associated with conventional multi-modal therapies, there is an urgent need for more novel approaches to treat ATRT, one such approach being immunotherapy. The recent rise of large-scale, multicenter interdisciplinary studies has delineated several molecular and genetic characteristics unique to ATRT. This review aims to describe currently available data on the tumor immune microenvironment of ATRT and its specific subtypes and to summarize the emerging clinical and preclinical results of immunotherapy-based approaches. It will also highlight the evolving knowledge of epigenetics on immunomodulation in this epigenetically influenced tumor, which may help guide the development of effective immunotherapeutic approaches in the future.
| S-EPMC10346396 | biostudies-literature
Project description:BackgroundRecurrent atypical teratoid/rhabdoid tumor (AT/RT) is, most often, a fatal pediatric malignancy with limited curative options.MethodsWe conducted a phase II study of Aurora kinase A inhibitor alisertib in patients aged <22 years with recurrent AT/RT. Patients received alisertib once daily (80 mg/m2 as enteric-coated tablets or 60 mg/m2 as liquid formulation) on Days 1-7 of a 21-day cycle until progressive disease (PD) occurred. Alisertib plasma concentrations were measured in cycle 1 on Days 1 (single dose) and 7 (steady state) and analyzed with noncompartmental pharmacokinetics. Trial efficacy end point was ≥10 participants with stable disease (SD) or better at 12 weeks.ResultsSD (n = 8) and partial response (PR) (n = 1) were observed among 30 evaluable patients. Progression-free survival (PFS) was 30.0% ± 7.9% at 6 months and 13.3% ± 5.6% at 1 year. One-year overall survival (OS) was 36.7% ± 8.4%. Two patients continued treatment for >12 months. PFS did not differ by AT/RT molecular groups. Neutropenia was the most common adverse effect (n = 23/30, 77%). The 22 patients who received liquid formulation had a higher mean maximum concentration (Cmax) of 10.1 ± 3.0 µM and faster time to Cmax (Tmax = 1.2 ± 0.7 h) than those who received tablets (Cmax = 5.7 ± 2.4 µM, Tmax = 3.4 ± 1.4 h).ConclusionsAlthough the study did not meet predetermined efficacy end point, single-agent alisertib was well tolerated by children with recurrent AT/RT, and SD or PR was observed in approximately a third of the patients.
| S-EPMC9925713 | biostudies-literature
Project description:Atypical teratoid/rhabdoid tumor (AT/RT) is an extremely malignant neoplasm in the central nervous system (CNS) which occurs in infancy and childhood. Recent studies suggested that CD133 could be considered a marker for brain cancer stem-like cells (CSCs). However, the role of CD133 in AT/RT has never been investigated. Herein we report the isolation of CD133-positive cells (CD133(+)), found to have the potential to differentiate into three germ layer tissues, from tissues of nine AT/RT patients. The migration/invasion/malignancy and radioresistant capabilities of CD133(+) were significantly augmented when compared to CD133(-). The clinical data showed that the amount of CD133(+) in AT/RTs correlated positively with the degree of resistance to radiation therapy. Using cDNA microarray analysis, the genotoxic-response profiles of CD133(+) and CD133(-) irradiated with 10 Gy ionizing radiation (IR) were analyzed 0.5, 2, 6, 12 and 24 h post-IR. We then validated these microarray data and showed increased phosphorylation after IR of p-ATM, p-RAD17, and p-CHX2 as well as increased expression of BCL-2 protein in CD133(+) compared to CD133(-). Furthermore, we found that CD133(+) can effectively resist IR with cisplatin- and/or TRAIL-induced apoptosis. Immunohistochemical analysis confirmed the up-regulated expression of p-ATM and BCL-2 proteins in IR-treated CD133(+) xenotransgrafts in SCID mice but not in IR-treated CD133(-). Importantly, the effect of IR in CD133(+) transplanted mice can be significantly improved by a combination of BCL-2 siRNA with debromohymenialdisine, an inhibitor of checkpoint kinases. In sum, this is the first report indicating that CD133(+) AT/RT cells demonstrate the characteristics of CSCs. The IR-resistant and anti-apoptotic properties in CD133(+) may reflect the clinical refractory malignancy of AT/RTs and thus the activated p-ATM pathway and BCL-2 expression in CD133(+) could be possible targets to improve future treatment of deadly diseases like AT/RT.
| S-EPMC2396792 | biostudies-literature