RARE DISEASE
Rhabdoid tumor
Rhabdoid tumor
Rhabdoid tumor
Synonyms: Malignant rhabdoid tumor
Synonyms: Malignant rhabdoid tumor
Synonyms: Malignant rhabdoid tumor
Drug discovery
3
drugs
With orphan designations
Overview
Rhabdoid tumor is a rare, highly aggressive malignancy primarily affecting infants and young children, with peak incidence under age 4 [1][4][12]. These tumors most commonly arise in the CNS (atypical teratoid rhabdoid tumors, ATRT), kidneys (malignant rhabdoid tumors, MRT), or soft tissues [1][6][17]. Over 90% involve biallelic SMARCB1 inactivation, disrupting chromatin remodeling and driving epigenetic dysregulation [1][8][19]. Prognosis remains poor despite multimodal therapy, with survival rates heavily influenced by age and primary site [4][12][16].
Burden
Therapies
Multimodal approach: Maximal safe resection + intensive chemotherapy (vincristine, cyclophosphamide, cisplatin/etoposide) + age-adjusted radiotherapy [1][3][13]
High-dose chemotherapy with autologous stem cell rescue for consolidation [1][3][5]
Protocols: COG ACNS0333 (surgery → chemo → HDCT) vs. Eu-Rhab (anthracycline-based regimens + early RT) [1][3][5]
Categories: rare neoplastic diseases
Research Papers
1,014 drug discovery papers about Rhabdoid tumor, with 8 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,014 drug discovery papers about Rhabdoid tumor, with 8 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-14 | Defective microhomology-mediated end joining in SMARCB1-deficient tumors.
Rhabdoid tumors (RTs) are highly aggressive cancers driven by biallelic mutation of SMARCB1, a core subunit of the BAF (SWI/SNF) complex. We found that SMARCB1-deficient tumors have a defect in the microhomology-mediated end joining (MMEJ) pathway, and SMARCB1 is essential for maintaining the protein level of the core MMEJ protein, DNA Polymerase theta (PolΘ). Mechanistically, SMARCB1 facilitates the nuclear export of the POLQ mRNA through its interaction with the nuclear pore complex. Interestingly, loss of MMEJ in RT cells leads to a compensatory activation of, and a hyper-dependence on, the Fanconi Anemia (FA)/BRCA pathway. Notably, degraders of RBM39, a splicing modulator, show strong antitumor efficacy in RT models in vitro and in vivo by disrupting FA/BRCA pathway. SMARCB1 and other cBAF/pBAF components are important for maintenance of MMEJ activity and PolΘ protein level, suggesting that BAF-deficient cancers more broadly may be treated by targeted inhibition of the FA/BRCA pathway.
2026-08-11 | Fingerroot-derived nanovesicles attenuate atypical teratoid rhabdoid tumor progression via modulation of Wnt signaling
Atypical teratoid rhabdoid tumor (ATRT) is an aggressive central nervous system tumor that primarily affects young children and has poor prognosis, highlighting the need for new treatment options. In this study, we examined how fingerroot exosome-like nanovesicles (FELNs) derived from Boesenbergia rotunda (L.) Mansf. affect ATRT and investigated their mechanisms of action. FELNs are round vesicles approximately 100 nm in diameter. Fluorescently labeled FELNs were taken up by cells and induced dose- and time-dependent cytotoxicity via apoptosis in ATRT cell lines BT12 and cisplatin-resistant BT16, with minimal effect in normal brain cells. Moreover, non-toxic concentrations of FELNs significantly decreased ATRT cell migration and invasion. Proteomic analysis revealed that FELNs disrupt multiple signaling pathways involved in ATRT development, including the Wnt/β-catenin pathway. FELN treatment reduced β-catenin protein levels and increased GSK-3β activity. It also decreased the expression of target genes, including c-myc, cyclin D1, axin2, and survivin . Overall, our findings demonstrate that FELNs exert anti-cancer effects in ATRT cells by inducing apoptosis and decreasing migration and invasion. These effects are partially mediated through the GSK-3β-dependent β-catenin pathway. The low toxicity in normal cells suggests that FELNs could be promising new therapeutic agents for cancer treatment.
2026-08-10 | DNMT3B plays antagonistic roles with SMARCB1 and is a targetable vulnerability in rhabdoid tumors.
Rhabdoid tumors (RTs) are highly aggressive pediatric cancers driven by the biallelic inactivation of the SMARCB1 tumor suppressor gene, the sole recurrent genetic alteration. SMARCB1 encodes a core subunit of the SWI/SNF chromatin remodeling complex; its loss disrupts epigenetic gene regulation, supporting the classification of RTs as prototypical epigenetically driven cancers and highlighting the therapeutic potential of targeting epigenetic modifiers. Notably, previous studies have reported the overexpression of DNMT3A and DNMT3B, enzymes responsible for de novo DNA methylation, in RTs. Using patient samples, cell lines, and an ex vivo brain organoid system, combined with immunohistochemistry and bioinformatics, we investigated the role of DNMT3 enzymes in RT progression. In a composite tumor case, SMARCB1-deficient and -proficient regions displayed distinct methylation profiles. SMARCB1 loss correlated with increased DNA methylation and DNMT3A/B overexpression. To assess their respective roles in RTs, we used CRISPR-Cas9 to knock out DNMT3A/B in a SMARCB1-inducible RT cell line. DNMT3B loss impaired viability more strongly than DNMT3A. DNMT3B knock-out and SMARCB1 re-expression regulated overlapping gene programs related to development and cell adhesion at methylation and transcriptional levels. We next demonstrated that the cytotoxicity of the DNMT inhibitor decitabine, which impairs RT cell growth in human iPS-derived cerebral organoids, is primarily mediated by DNMT3B. These results show that DNMT3B plays a key role in the cascade of epigenetic effects following SMARCB1 loss and is pivotal in the RT sensitivity to decitabine; our study therefore supports the development of DNMT3B-specific inhibitors for RT.
2026-08-08 | Nuclear export inhibition activates TP53 pathways and is a potent therapeutic strategy in atypical teratoid rhabdoid tumors
Abstract Background Atypical teratoid/rhabdoid tumor (ATRT) is an aggressive central nervous system tumor mostly affecting young children. Improved and less toxic therapies for children with ATRT are imperative due to the toxicities associated with current treatments. Furthermore, existing therapies do not address the underlying genetic drivers of ATRT. In this study, we sought to determine whether exportin-1 (XPO1) is a genetic dependency and therapeutic target in ATRT. Methods We utilized an integrative approach harnessing patient-derived ATRT cell lines, functional genomics, pharmacologic assays, transcriptomics, and in vivo intracranial xenograft models to systematically test the hypothesis that XPO1 is a novel dependency in ATRT. Results Analysis of RNA-sequencing datasets revealed high XPO1 expression in ATRT cells compared to other pediatric brain tumor cell lines. Both CRISPR/Cas9 genetic knockdown and pharmacologic inhibition of XPO1 using six selective inhibitors of nuclear export (SINEs) in patient-derived ATRT cells led to significant reduction in cell viability and proliferation. Furthermore, we observed increased apoptosis, G0 phase cell cycle arrest, and upregulation of TP53 signaling pathways in cells treated with the SINE selinexor. Consistently, our transcriptomic data revealed the upregulation of apoptosis and TP53 signaling pathways and concomitant depletion of cell cycle gene sets. In vivo, selinexor in combination with radiation and cyclophosphamide led to significant reduction in tumor volume and increased animal survival in intracranial ATRT xenograft models. Conclusions Our data reveal XPO1 as a novel genetic dependency and potent therapeutic target in ATRT.
2026-07-27 | Intracerebroventricular B7-H3-targeting CAR T cells for non-pontine DMG and recurrent/refractory pediatric CNS tumors: a phase 1 trial.
High-grade central nervous system (CNS) tumors carry a poor prognosis with limited curative options if first-line therapy fails. B7-H3 is expressed in many of these tumors, and chimeric antigen receptor (CAR) T cell therapy is an emerging immunotherapeutic strategy. BrainChild-03 (NCT04185038) is a single-center, dose-escalation phase 1 study of repeated intracerebroventricular (ICV) B7-H3 CAR T cells in children and young adults with recurrent/refractory CNS tumors (Arms A, B) and diffuse intrinsic pontine glioma (DIPG, Arm C). Here, we report results from Arm B, in which patients with refractory/relapsed CNS tumors or pre- or post-progression non-pontine diffuse midline glioma (DMG) received repeated ICV infusions. Primary objectives were feasibility and safety/tolerability; secondary objectives included CAR T cell detection, disease response, and survival. Of 36 enrolled patients (atypical teratoid rhabdoid tumor n = 5, DMG n = 8, embryonal tumor with multilayer rosettes n = 2, ependymoma n = 4, high-grade glioma n = 6, medulloblastoma n = 8, pineoblastoma n = 3), manufacturing was successful for 35 patients, 26 of whom received therapy. Median age was 10 years (range 1-26). Dose escalation from 1 × 107 to 10 × 107 CAR T cells/dose identified this dose as the maximally tolerated dose regimen, with no dose-limiting toxicities observed. Across 181 total doses (median 7/patient), common adverse events included headache (n = 26), fever (n = 15), and nausea (n = 14). Median survival from first infusion was 11.5 months, ranging from 3.2 months (pineoblastoma, HGG) to 21.4 months (ependymoma); two patients achieved a partial response. Repeated ICV B7-H3 CAR T cell dosing is feasible and tolerable across a spectrum of pediatric CNS tumors, supporting continued investigation in future trials.
2026-08-14 | Defective microhomology-mediated end joining in SMARCB1-deficient tumors.
Rhabdoid tumors (RTs) are highly aggressive cancers driven by biallelic mutation of SMARCB1, a core subunit of the BAF (SWI/SNF) complex. We found that SMARCB1-deficient tumors have a defect in the microhomology-mediated end joining (MMEJ) pathway, and SMARCB1 is essential for maintaining the protein level of the core MMEJ protein, DNA Polymerase theta (PolΘ). Mechanistically, SMARCB1 facilitates the nuclear export of the POLQ mRNA through its interaction with the nuclear pore complex. Interestingly, loss of MMEJ in RT cells leads to a compensatory activation of, and a hyper-dependence on, the Fanconi Anemia (FA)/BRCA pathway. Notably, degraders of RBM39, a splicing modulator, show strong antitumor efficacy in RT models in vitro and in vivo by disrupting FA/BRCA pathway. SMARCB1 and other cBAF/pBAF components are important for maintenance of MMEJ activity and PolΘ protein level, suggesting that BAF-deficient cancers more broadly may be treated by targeted inhibition of the FA/BRCA pathway.
2026-08-11 | Fingerroot-derived nanovesicles attenuate atypical teratoid rhabdoid tumor progression via modulation of Wnt signaling
Atypical teratoid rhabdoid tumor (ATRT) is an aggressive central nervous system tumor that primarily affects young children and has poor prognosis, highlighting the need for new treatment options. In this study, we examined how fingerroot exosome-like nanovesicles (FELNs) derived from Boesenbergia rotunda (L.) Mansf. affect ATRT and investigated their mechanisms of action. FELNs are round vesicles approximately 100 nm in diameter. Fluorescently labeled FELNs were taken up by cells and induced dose- and time-dependent cytotoxicity via apoptosis in ATRT cell lines BT12 and cisplatin-resistant BT16, with minimal effect in normal brain cells. Moreover, non-toxic concentrations of FELNs significantly decreased ATRT cell migration and invasion. Proteomic analysis revealed that FELNs disrupt multiple signaling pathways involved in ATRT development, including the Wnt/β-catenin pathway. FELN treatment reduced β-catenin protein levels and increased GSK-3β activity. It also decreased the expression of target genes, including c-myc, cyclin D1, axin2, and survivin . Overall, our findings demonstrate that FELNs exert anti-cancer effects in ATRT cells by inducing apoptosis and decreasing migration and invasion. These effects are partially mediated through the GSK-3β-dependent β-catenin pathway. The low toxicity in normal cells suggests that FELNs could be promising new therapeutic agents for cancer treatment.
2026-08-10 | DNMT3B plays antagonistic roles with SMARCB1 and is a targetable vulnerability in rhabdoid tumors.
Rhabdoid tumors (RTs) are highly aggressive pediatric cancers driven by the biallelic inactivation of the SMARCB1 tumor suppressor gene, the sole recurrent genetic alteration. SMARCB1 encodes a core subunit of the SWI/SNF chromatin remodeling complex; its loss disrupts epigenetic gene regulation, supporting the classification of RTs as prototypical epigenetically driven cancers and highlighting the therapeutic potential of targeting epigenetic modifiers. Notably, previous studies have reported the overexpression of DNMT3A and DNMT3B, enzymes responsible for de novo DNA methylation, in RTs. Using patient samples, cell lines, and an ex vivo brain organoid system, combined with immunohistochemistry and bioinformatics, we investigated the role of DNMT3 enzymes in RT progression. In a composite tumor case, SMARCB1-deficient and -proficient regions displayed distinct methylation profiles. SMARCB1 loss correlated with increased DNA methylation and DNMT3A/B overexpression. To assess their respective roles in RTs, we used CRISPR-Cas9 to knock out DNMT3A/B in a SMARCB1-inducible RT cell line. DNMT3B loss impaired viability more strongly than DNMT3A. DNMT3B knock-out and SMARCB1 re-expression regulated overlapping gene programs related to development and cell adhesion at methylation and transcriptional levels. We next demonstrated that the cytotoxicity of the DNMT inhibitor decitabine, which impairs RT cell growth in human iPS-derived cerebral organoids, is primarily mediated by DNMT3B. These results show that DNMT3B plays a key role in the cascade of epigenetic effects following SMARCB1 loss and is pivotal in the RT sensitivity to decitabine; our study therefore supports the development of DNMT3B-specific inhibitors for RT.
2026-08-08 | Nuclear export inhibition activates TP53 pathways and is a potent therapeutic strategy in atypical teratoid rhabdoid tumors
Abstract Background Atypical teratoid/rhabdoid tumor (ATRT) is an aggressive central nervous system tumor mostly affecting young children. Improved and less toxic therapies for children with ATRT are imperative due to the toxicities associated with current treatments. Furthermore, existing therapies do not address the underlying genetic drivers of ATRT. In this study, we sought to determine whether exportin-1 (XPO1) is a genetic dependency and therapeutic target in ATRT. Methods We utilized an integrative approach harnessing patient-derived ATRT cell lines, functional genomics, pharmacologic assays, transcriptomics, and in vivo intracranial xenograft models to systematically test the hypothesis that XPO1 is a novel dependency in ATRT. Results Analysis of RNA-sequencing datasets revealed high XPO1 expression in ATRT cells compared to other pediatric brain tumor cell lines. Both CRISPR/Cas9 genetic knockdown and pharmacologic inhibition of XPO1 using six selective inhibitors of nuclear export (SINEs) in patient-derived ATRT cells led to significant reduction in cell viability and proliferation. Furthermore, we observed increased apoptosis, G0 phase cell cycle arrest, and upregulation of TP53 signaling pathways in cells treated with the SINE selinexor. Consistently, our transcriptomic data revealed the upregulation of apoptosis and TP53 signaling pathways and concomitant depletion of cell cycle gene sets. In vivo, selinexor in combination with radiation and cyclophosphamide led to significant reduction in tumor volume and increased animal survival in intracranial ATRT xenograft models. Conclusions Our data reveal XPO1 as a novel genetic dependency and potent therapeutic target in ATRT.
2026-07-27 | Intracerebroventricular B7-H3-targeting CAR T cells for non-pontine DMG and recurrent/refractory pediatric CNS tumors: a phase 1 trial.
High-grade central nervous system (CNS) tumors carry a poor prognosis with limited curative options if first-line therapy fails. B7-H3 is expressed in many of these tumors, and chimeric antigen receptor (CAR) T cell therapy is an emerging immunotherapeutic strategy. BrainChild-03 (NCT04185038) is a single-center, dose-escalation phase 1 study of repeated intracerebroventricular (ICV) B7-H3 CAR T cells in children and young adults with recurrent/refractory CNS tumors (Arms A, B) and diffuse intrinsic pontine glioma (DIPG, Arm C). Here, we report results from Arm B, in which patients with refractory/relapsed CNS tumors or pre- or post-progression non-pontine diffuse midline glioma (DMG) received repeated ICV infusions. Primary objectives were feasibility and safety/tolerability; secondary objectives included CAR T cell detection, disease response, and survival. Of 36 enrolled patients (atypical teratoid rhabdoid tumor n = 5, DMG n = 8, embryonal tumor with multilayer rosettes n = 2, ependymoma n = 4, high-grade glioma n = 6, medulloblastoma n = 8, pineoblastoma n = 3), manufacturing was successful for 35 patients, 26 of whom received therapy. Median age was 10 years (range 1-26). Dose escalation from 1 × 107 to 10 × 107 CAR T cells/dose identified this dose as the maximally tolerated dose regimen, with no dose-limiting toxicities observed. Across 181 total doses (median 7/patient), common adverse events included headache (n = 26), fever (n = 15), and nausea (n = 14). Median survival from first infusion was 11.5 months, ranging from 3.2 months (pineoblastoma, HGG) to 21.4 months (ependymoma); two patients achieved a partial response. Repeated ICV B7-H3 CAR T cell dosing is feasible and tolerable across a spectrum of pediatric CNS tumors, supporting continued investigation in future trials.
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Drug Discovery Landscape
3 orphan drug designations for Rhabdoid tumor.
3 orphan drug designations for Rhabdoid tumor.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
N-hydroxy-N-(methylacylfulvene)urea | small molecules | FDA | 2024-10-28 | — | Lantern Pharma Inc. |
O-18F-fluoroethyl-L-tyrosine | small molecules | FDA | 2019-05-08 | — | Advanced Imaging Projects, LLC |
tazemetostat | small molecules | FDA | 2016-02-04 | — | Epizyme Inc. |
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