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At least 19 recordsLinked to original sources
PubMed2026

Spatial Proteomic Profiling, a Novel Method for Detecting Diagnostic and Prognostic Proteins in Pediatric Sarcoma.

Pediatric sarcomas comprise approximately 10% of all childhood solid malignancies and are characterized by distinct genetic and proteomic alterations that have potential diagnostic, prognostic, and therapeutic significance. We have utilized digital spatial profiling (DSP) to identify protein expression in pediatric Ewing sarcoma (ES), Osteosarcoma (OS), Alveolar rhabdomyosarcoma (ARMS), and Embryonal rhabdomyosarcoma (ERMS), in association with clinical outcomes. Formalin-fixed, paraffin-embedded sections from a tissue microarray block containing eight ES, eight OS, five ARMS, and three ERMS cases were subjected to proteomic DSP on a GeoMx NanoString platform yielding information on expression of 580 proteins. Proteins related to epigenetic regulation, signaling pathways, and mesenchymal differentiation were broadly expressed across all tumor types. Tumor-specific protein profiles were defined based on highly expressed proteins. Differentially expressed proteins include Cyclin D1 in ES, S100A4 in OS and IKKi/IKKe in ARMS and ERMS. Immunohistochemical validation confirmed variable expression of H3K27me3 across the tumors, and elevated expression of Cyclin D1 in ES and S100 in OS. These findings underscore the utility of DSP as a high-resolution proteomic tool for the identification of clinically relevant biomarkers in pediatric sarcomas. The results provide a foundation for further investigation of candidate proteins with potential diagnostic, prognostic, and therapeutic applications.

Humans↗
PubMed2026

Pediatric sarcomas: challenges and opportunities.

Pediatric sarcomas are a heterogeneous group of rare mesodermal malignancies. These cancers, which affect children from infancy through adolescence and young adulthood, are in general challenging to treat with currently available therapies. Biologically, many are characterized by quiet genomes, fusion oncoproteins, immune "cold" microenvironments, and vast epigenetic deregulation that contributes to diverse and complex mechanistic drivers. Multifaceted advancements in research strategies, including high-throughput screening, new model systems, surfaceome profiling, and study of oncogenic fusion condensates have led to new opportunities for understanding the biology of pediatric sarcomas. To continue to make progress for these difficult to treat cancers, it will be critical to continue to improve access to bioinformatic data, approach patient care using innovative clinical trial frameworks, and foster interdisciplinary partnerships among medicinal chemists, scientists, clinicians, advocates, and industry partners.

Humans↗
PubMed2026

Comprehensive Multiplatform Tyrosine Kinase Profiling Reveals Novel Actionable FGFR Aberrations across Sarcomas Affecting the Young.

Limited targeted agents are approved for pediatric sarcomas. Tyrosine kinase (TK) inhibitors (TKi) have shown clinical efficacy in some, but not all, young patients with sarcoma. A major obstacle preventing further advances and clinical implementation is the lack of predictive response biomarkers to guide TK-targeted treatments. TK-activating fusions or mutations are rare in these patients. RNA overexpression of TKs is a frequent feature. The unresolved question is when upregulated TK expression is associated with kinase activation and signaling dependence. We explored the TK molecular landscape of 107 patients with sarcoma from the ZERO Childhood Cancer Precision Medicine Program (ZERO) using whole-genome and -transcriptome sequencing. Phosphoproteomic analyses of tyrosine phosphorylation (pY) and functional in vitro and in vivo assays were performed in cell lines and patient-derived xenografts (PDX). Our analysis shows that although novel genomic driver lesions are rare, when present they are therapeutically actionable as exemplified by a novel LSM1-FGFR1 fusion identified in a patient with osteosarcoma. We further show that in certain contexts, TK RNA expression can indicate TK pathway activity and predict TKi sensitivity. We highlight the utility of FGFR inhibitors in PAX3-FOXO1 fusion-positive rhabdomyosarcomas (FP-RMS) characterized by high FGFR4 and FGF8 RNA expression levels and FGFR4 activation (FGFR4_pY). We demonstrate marked tumor growth inhibition in all FP-RMS PDXs treated with single-agent FGF401 (FGFR4-specific inhibitor) and single-agent lenvatinib (multikinase FGFR inhibitor) and report a clinical response to lenvatinib in a patient with relapsed metastatic FP-RMS. Altogether, we identified new patients with sarcoma who may benefit from FGFR inhibitors, most notably FP-RMS via FGFR4/FGF8 coexpression.

Journal Article↗
PubMed2025

PAX3-FOXO1 Drives Targetable Cell State-Dependent Metabolic Vulnerabilities in Rhabdomyosarcoma.

UNLABELLED: PAX3-FOXO1, an oncogenic transcription factor, drives a particularly aggressive subtype of rhabdomyosarcoma (RMS) by enforcing gene expression programs that support malignant cell states. In this study, we show that PAX3-FOXO1+ RMS cells exhibit altered pyrimidine metabolism and increased dependence on enzymes involved in de novo pyrimidine synthesis, including dihydrofolate reductase (DHFR). Consequently, PAX3-FOXO1+ cells display increased sensitivity to inhibition of DHFR by the chemotherapeutic drug methotrexate, and this dependence is rescued by provision of pyrimidine nucleotides. Methotrexate treatment mimics the metabolic and transcriptional impact of PAX3-FOXO1 silencing, reducing expression of genes related to PAX3-FOXO1-driven malignant cell states. Accordingly, methotrexate treatment slows the growth of multiple PAX3-FOXO1+ tumor xenograft models but not their fusion-negative counterparts. Taken together, these data demonstrate that PAX3-FOXO1 induces cell states characterized by altered pyrimidine dependence and nominates methotrexate as an addition to the current therapeutic arsenal for treatment of these malignant pediatric tumors. SIGNIFICANCE: PAX3-FOXO1+ rhabdomyosarcoma cells and tumors exhibit increased sensitivity to DHFR inhibition via methotrexate, identifying a potential therapeutic vulnerability that can be exploited to treat this aggressive pediatric sarcoma.

Humans↗
PubMed2025

Relapsed rhabdomyosarcoma: treatment recommendations from the European pediatric soft tissue sarcoma study group (EpSSG).

At least one-third of patients with localized rhabdomyosarcoma (RMS) and 60-70% of patients with metastatic RMS experience progressive disease or relapse. Following relapse, outcomes generally remain poor with limited treatment options and a high risk of subsequent recurrence. Optimal treatment requires a multidisciplinary approach incorporating chemotherapy with local control. Given the complexity of managing relapsed RMS and the challenges in developing effective treatment strategies, we aim to present clear and practical recommendations on the management of these patients across Europe. These recommendations were developed collaboratively by a group of pediatric and adolescent sarcoma experts from the European paediatric Soft Tissue Sarcoma Study Group. A careful review of the literature was performed to ensure that wherever possible recommendations are supported by the results of clinical trials or substantive retrospective reports. Such recommendations provide a standardized approach to managing relapsed cases, improving patient outcomes and offering a framework for clinicians to make informed decisions.

Humans↗
PubMed2024

STAG2 loss in Ewing sarcoma alters enhancer-promoter contacts dependent and independent of EWS::FLI1.

Cohesin complexes carrying STAG1 or STAG2 organize the genome into chromatin loops. STAG2 loss-of-function mutations promote metastasis in Ewing sarcoma, a pediatric cancer driven by the fusion transcription factor EWS::FLI1. We integrated transcriptomic data from patients and cellular models to identify a STAG2-dependent gene signature associated with worse prognosis. Subsequent genomic profiling and high-resolution chromatin interaction data from Capture Hi-C indicated that cohesin-STAG2 facilitates communication between EWS::FLI1-bound long GGAA repeats, presumably acting as neoenhancers, and their target promoters. Changes in CTCF-dependent chromatin contacts involving signature genes, unrelated to EWS::FLI1 binding, were also identified. STAG1 is unable to compensate for STAG2 loss and chromatin-bound cohesin is severely decreased, while levels of the processivity factor NIPBL remain unchanged, likely affecting DNA looping dynamics. These results illuminate how STAG2 loss modifies the chromatin interactome of Ewing sarcoma cells and provide a list of potential biomarkers and therapeutic targets.

Sarcoma, Ewing↗
PubMed2026

DNA Methylation Profiling of Pediatric Ectomesenchymoma Supports Embryonal Rhabdomyosarcoma-Like Epigenetic Identity.

Ectomesenchymoma is a rare, biphenotypic pediatric tumor combining rhabdomyoblastic and neuroectodermal differentiation. We characterize two novel cases through integrated genomics and the first report of genome-wide DNA methylation profiling. Both tumors harbored RAS-pathway mutations (HRAS p.Gly13Arg; NRAS p.Gln61His). Methylation analysis, including microdissected components, consistently aligned ectomesenchymoma with the embryonal rhabdomyosarcoma superfamily, revealing a shared myogenic epigenetic program despite neural differentiation. Shared copy-number profiles across distinct histological regions supported a monoclonal origin. Overall, our data support a close biological relationship between ectomesenchymoma and embryonal rhabdomyosarcoma and indicate that RAS-pathway testing and methylation profiling can significantly refine diagnostic precision.

Humans↗
PubMed2025

EWS::WT1 Isoform-Dependent Regulation of Neogenes in Desmoplastic Small Round Cell Tumors.

Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive sarcoma characterized by the pathognomonic EWS::WT1 fusion protein (FP), an oncogenic chimeric transcription factor (OCTF) resulting from the t(11;22)(p13;q12) translocation. Recent studies have identified "neogenes" (NGs), genes normally silent in normal tissues but transcriptionally activated by OCTFs, as potential tumor-specific markers in fusion-driven cancers. In this study, we investigated the expression and regulation of DSRCT-specific NGs (DSRCT_NGs) using multimodal data across different cohorts of patients, PDX, and cell line data. We evaluated bulk and single-nucleus RNA sequencing of patient specimens from MD Anderson Cancer Center, revealing the robust ability for DSRCT_NGs to distinguish FP-positive DSRCT from samples failing detection of the EWS::WT1 FP. To elucidate the regulatory role of the EWS::WT1 FP in driving NG expression, we performed knockdown experiments in four DSRCT cell lines. This consistently resulted in a reduction of DSRCT_NG expression. Isoform-specific expression of EWS::WT1 in LP9 and MeT-5A mesothelial cells revealed that the E-KTS isoform of EWS::WT1 predominantly drives DSRCT_NG expression. Mechanistically, ATAC-seq and ChIP-seq analyses demonstrated that EWS::WT1 directly binds to accessible chromatin regions near NG transcription start sites, enriched for WT1 motifs and active histone marks. Integration of Hi-ChIP data further revealed that EWS::WT1 facilitates long-range enhancer-promoter looping at DSRCT_NG loci, promoting the expression of nearby genes. Collectively, these findings establish DSRCT_NGs as direct transcriptional outputs of the EWS::WT1 FP and implicate their loci as regulatory regions of the DSRCT transcriptome. Their fusion-dependent expression, chromatin accessibility, and promoter-enhancer connectivity underscore their potential utility as highly specific biomarkers and therapeutic targets in DSRCT.

DSRCT↗
PubMed1978

[Contribution to central nervous system tumor diagnosis by means of cytocentrifuged cerebrospinal fluid].

The cytocentrifugation of the liquor cerebrospinalis provides a useful diagnostic tool to differentiate benign from malign diseases of the central nervous system. The method is illustrated with liquor analyses in the field of pediatric oncology: medulloblastoma, leptomeninx sarcoma, plexuspapilloma, astrocytoma, Abt-Letterer-Siwe, ALL, reticulum cell sarcoma, Ewing sarcoma, retinoblastoma. The speed and ease of the processing, the highest possible cellular yield and the good preservation of the cellular characteristics are great advantages of this new method.

Brain Neoplasms↗
PubMed2026

Circulating IGF2BP3 enables risk stratification and predicts treatment response in Ewing sarcoma.

Ewing sarcoma (EWS), the second most common pediatric bone tumor, presents with a markedly heterogeneous clinical spectrum and optimal risk stratification is therefore crucial for improving treatment outcomes. The RNA-binding protein IGF2BP3 is a critical oncogenic driver of EWS malignancy. This study evaluates the clinical utility of circulating IGF2BP3 as a biomarker to predict treatment response and risk of disease progression in patients with EWS. Plasma samples from 60 patients with EWS diagnosed and treated at the IRCCS Rizzoli Orthopedic Institute (Bologna, Italy) were collected at diagnosis before treatment initiation and/or after induction chemotherapy. For 51 of these patients, blood was collected at diagnosis, prior to any treatments. For 25 patients, blood samples were available at diagnosis and before surgical intervention, allowing longitudinal analysis in the same patient. For 9 patients, blood was collected only after preoperative chemotherapy, before surgical intervention. Circulating IGF2BP3 levels were quantified using a highly specific and sensitive ELISA assay. Plasma samples from healthy donors served as controls. IGF2BP3 plasma levels were correlated with IGF2BP3 tumor tissue expression, established clinical risk factors, and cumulative incidence of relapse using univariable and multivariable analyses. Plasma IGF2BP3 levels were significantly elevated in patients with EWS compared with healthy controls, with a subset of patients (22/51, 43.2%) exhibiting clinically relevant concentrations. Circulating IGF2BP3 levels reflected tumor expression of the molecule and provided additional prognostic information beyond standard clinicopathologic features. The prognostic impact of circulating IGF2BP3 was primarily observed in patients with localized disease, in whom elevated levels were identified as a significant adverse prognostic factor for disease-specific survival (hazard ratio, 10.63; 95% CI, 1.27-88.62; P = 0.029). Longitudinal monitoring demonstrated that persistence of IGF2BP3 in plasma after induction chemotherapy was a strong predictor of poor clinical outcomes. Circulating IGF2BP3 represents a valuable biomarker for early risk stratification in EWS, particularly in patients with localized disease. Although this is single-marker assay, the expression of the molecule may impact on the fate of many mRNAs. We present an accurate, simple, cost-effective and easy clinical applicable tool to support risk-adapted therapeutic interventions. The limited number of employed patients warrants the need of larger cohorts for validation.

Humans↗
PubMed2026

Integrative Multiomics and Drug Sensitivity Profiling Reveal Potential Biomarkers and Therapeutic Strategies in Pediatric Solid Tumors.

UNLABELLED: Cure rates for childhood malignancies using established therapy protocols have increased to an average of 80% but have reached a plateau. Moreover, survival rates are particularly low for some pediatric tumors-such as high-risk group 3 medulloblastomas, osteosarcomas, Ewing sarcomas, high-risk neuroblastomas, and high-grade gliomas-and dismal for patients with relapsed malignancies. A functional drug response profiling platform for pediatric solid and brain tumors has been established within the INFORM program to identify patient-specific vulnerabilities and biomarkers and to unravel molecular mechanisms associated with drug response profiles for clinical translation. In this study, we performed a multiomics analysis using drug sensitivity profiles, as well as genomic and transcriptomic data, of 81 pediatric solid tumor samples. The integrative analysis suggested two multiomics signatures associated with drug sensitivity. One signature distinguished neuroblastoma samples with sensitivity to navitoclax, a BCL2 family inhibitor. A second signature was specific to a subset of Wilms tumors harboring the SIX1 (Q177R) hotspot mutation that displayed high expression of MGAM, PTPN14, STAT4, and KDM2B and high sensitivity to MEK inhibitors. A patient-specific causal interaction network analysis suggested possible molecular interactions between MEK inhibitors and the SIX1 mutation in Wilms tumor samples. In conclusion, the integration of drug sensitivity profiling and multiomics data revealed potential biomarkers that may be associated with drug sensitivity in pediatric solid tumors. Patient-specific causal interaction network analysis further elucidated the interaction between inhibitors and signature biomarkers, providing insights that may inform clinical translation. SIGNIFICANCE: The combination of multiomics analysis and drug sensitivity profiling identified two signatures related to drug sensitivity in pediatric solid tumors, contributing to the advancement of functional precision medicine and personalized treatment strategies. This article is part of a special series: Driving Cancer Discoveries with Computational Research, Data Science, and Machine Learning/AI .

Humans↗
PubMed1978

Undifferentiated (embryonal) sarcoma of the liver: report of 31 cases.

Thirty-one cases of undifferentiated (embryonal) sarcoma of the liver are presented. The tumor is found predominantly in the pediatric age group, the majority of patients (51.6%) being between 6 and 10 years of age. An abdominal mass and pain are the usual presenting symptoms. Radiographic examination is nonspecific except to demonstrate a space-occupying lesion of the liver. The tumors are large, single, usually globular and well demarcated, and have multiple cystic areas of hemorrhage, necrosis, and gelatinous degeneration. Histologic examination shows a pseudocapsule partially separating the normal liver from undifferentiated sarcomatous cells that, near the periphery of the tumor, surround entrapped hyperplastic or degenerating bile duct-like structures. Eosinophilic globules that are PAS positive are usually found within and adjacent to tumor cells. Areas of necrosis and hemorrhage are prominent. The prognosis is poor, with a median survival of less than 1 year following diagnosis.

Adolescent↗
PubMed1978

Experience with "second-look" operations in pediatric solid tumors.

"Second-look" operations were performed in 32 infants and children with initially unresectable or recurrent solid tumors treated with combination chemotherapy and/or irradiation. Tumors were resectable in 26 of 32 cases (81%). These procedures often yielded information affecting staging and treatment. Disease-free survival was achieved in 18 of 32 patients (56%). Mortality was related to progressive disease in seven cases and opportunistic infections due to immunosuppression in three. Four additional patients are alive with evidence of persistent tumor. Second-look procedures were beneficial in patients with Wilms' tumor previously operated upon by a flank approach and in children with bilateral tumors. These procedures were particularly useful in children with stage III localized neuroblastoma and cases of metastatic neuroblastoma that respond to chemotherapy. Second-look operations were also useful in selected cases of rhabdomyosarcoma, teratoma, and Ewing's sarcoma. These observations suggest that combination chemotherapy has increased the use of second-look operations in a variety of less favorable (e.g. initially unresectable or recurrent) pediatric solid tumors.

Antineoplastic Agents↗
PubMed1976

Gallium-67 scans in children with solid tumors.

Twenty pediatric patients with malignant disease were studied by whole body gallium scans. Seven had Hodgkin's disease, five had soft tissue sarcomas, three had neuroblastomas, two had Wilm's tumors, and one each had a hepatoblastoma, embryonal cell carcinoma, and sacrococcygeal teratoma. Of 50 sites studied, there was a true positive result in 17%, and in 58% there were false negative results. The method served best in patients with Hodgkin's disease, where the true positive rate was 64%. In no instance did the gallium scan affect the clinical management of a patient.

Adolescent↗
PubMedDate not supplied

cis-Dichlorodiammineplatinum(II) in childhood cancer.

cis-Dichlorodiammineplatinum(II) (cis-platinum) was evaluated in three separate studies at Roswell Park Memorial Institute in children and adolescents with cancer. In the first study, 16 patients with a variety of solid tumors were treated. Objective responses were seen in patients with neuroblastoma, osteogenic sarcoma, seminoma, and medullary carcinoma of the thyroid. In the second study, five of eight patients with far-advanced osteogenic sarcoma showed objective responses to cis-platinum. In the third study, cis-platinum and Adriamycin were employed as primary adjuvant chemotherapy along with surgery in osteogenic sarcoma. Nine of ten patients have remained disease-free from 8 to 31 months (mean, 19 months). cis-Platinum is an active agent in pediatric tumors.

Adolescent↗