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Atypical teratoid rhabdoid tumors (ATRTs): the British Columbia's Children's Hospital's experience, 1986-2006.

ABSTRACT: As "atypical teratoid rhabdoid tumors" (ATRTs) may mimic "small round blue cell tumors" (SRBCT), we reexamined our ATRT experience focusing upon INI-1 immunohistochemistry (IHC). All high-grade pediatric brain tumors occurring from 1986-2006 at our institution underwent INI-1 IHC. Clinicopathologic data from each INI-1 immunonegative case were reviewed. Additional genetic, epigenetic and IHC analyses (including interrogation of INI-1 and CLDN6) were performed on a subset of the INI-1 immunonegative cases. Twelve INI-1 IHC negative tumors were identified retrospectively, of which only two previously carried the diagnosis of ATRT. Overall, the clinicopathologic and genetic data supported the assertion that all 12 cases represented ATRT. Unexpectedly, three long-term survivors (4.2, 7.0 and 8.5 years) were identified. As hypothesized, "teratoid" and "rhabdoid" histologic features were relatively infrequent despite gross total resections in some cases. Methylation specific polymer chain reaction (PCR) (MSP) revealed a uniform methylation pattern across all cases and gene promoters tested (ie, MGMT, HIC1, MLH3 and RASSF1); notably, all cases demonstrated unmethylated MGMT promoters. Our data demonstate that a primitive non-rhabdoid histophenotype is common among ATRTs and highlights the diagnostic importance of INI-1 IHC. Epigenetically, the MGMT promoter is usually unmethylated in ATRT, suggesting that potential temozolomide-based chemotherapy may be of limited efficacy.

SUBMITTER: Fleming AJ

PROVIDER: S-EPMC8057629 | biostudies-literature |

REPOSITORIES: biostudies-literature

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ATYPICAL TERATOID RHABDOID TUMOUR

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Wnt pathway in atypical teratoid rhabdoid tumors.

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Project description:Atypical teratoid/rhabdoid tumors (AT/RTs) are lethal central nervous system tumors, which are primarily diagnosed in infants. Current treatments for AT/RTs include surgery, radiotherapy, and chemotherapy; these treatments have poor prognoses and challenging side effects. The pivotal genetic event in AT/RT pathogenesis comprises the inactivation of SMARCB1 or SMARCA4. Recent epigenetic studies have demonstrated mutual and subtype-specific epigenetic derangements that drive tumorigenesis; the exploitation of these potential targets might improve the dismal treatment outcomes of AT/RTs. This review aims to summarize the literature concerning targeted molecular therapies for pediatric AT/RTs.

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Ribavirin as a potential therapeutic for atypical teratoid/rhabdoid tumors.

Project description:Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive, malignant tumors and are the most common malignant brain tumor in children under 6 months of age. Currently, there is no standard treatment for AT/RT. Recent studies have reported potential anti-tumoral properties of ribavirin, a guanosine analog and anti-viral molecule approved by the Food and Drug Administration for treatment of hepatitis C. We previously demonstrated that ribavirin inhibited glioma cell growth in vitro and in vivo. Based on these results and the fact that no pre-clinical model of ribavirin in AT/RT exists, we decided to investigate the effect of ribavirin on several human AT/RT cell lines (BT12, BT16, and BT37) both in vitro and in vivo. We provide evidence that ribavirin has a significant impact on AT/RT cell growth and increases cell cycle arrest and cell death, potentially through modulation of the eIF4E and/or EZH2 pathways. Interestingly, using scratch wound and transwell Boyden chamber assays, we observed that ribavirin also impairs AT/RT cell migration, invasion, and adhesion. Finally, we demonstrate that ribavirin significantly improves the survival of mice orthotopically implanted with BT12 cells. Our work establishes that ribavirin is effective against AT/RT by decreasing tumoral cell growth and dissemination and could represent a new therapeutic option for children with this deadly disease.

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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 (?-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 ?-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.

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