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Histopathology Jan 2022Rhabdomyosarcomas comprise the single largest category of soft tissue sarcomas in children and adolescents in the United States, occurring in 4.5 million people aged... (Review)
Review
Rhabdomyosarcomas comprise the single largest category of soft tissue sarcomas in children and adolescents in the United States, occurring in 4.5 million people aged below 20 years. Based on the clinicopathological features and genetic abnormalities identified, rhabdomyosarcomas are classified into embryonal, alveolar, spindle cell/sclerosing and pleomorphic subtypes. Each subtype shows distinctive morphology and has characteristic genetic abnormalities. This review discusses the evolution of the classification of rhabdomyosarcoma to the present day, together with a discussion of key histomorphological and genetic features of each subtype and the diagnostic approach to these tumours.
Topics: Biomarkers, Tumor; Forkhead Box Protein O1; Humans; MyoD Protein; Rhabdomyosarcoma; Soft Tissue Neoplasms
PubMed: 34958505
DOI: 10.1111/his.14449 -
Cancer Management and Research 2022This paper describes the standard of care for patients with non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) and the therapeutic recommendations developed by the... (Review)
Review
This paper describes the standard of care for patients with non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) and the therapeutic recommendations developed by the European paediatric Soft tissue sarcoma Study Group (EpSSG). NRSTS form a very mixed group of mesenchymal extraskeletal malignancies. Their rarity, heterogeneity, and aggressiveness make the management of children and adolescents with these tumors complex and challenging. The overall cure rate for patients with NRSTS is around 70%, but survival depends on several prognostic variables, such as histotype and tumor grade, extent of disease and stage, tumor size, and tumor site. While surgery remains the mainstay of treatment for most of these tumors, a multimodal therapeutic approach including radiotherapy and chemotherapy is required in many cases. The EpSSG NRSTS 2005 study was the first prospective protocol tailored specifically to NRSTS. Together with the ARST0332 study developed by the North-American Soft Tissue Sarcoma Committee of the Children's Oncology Group (COG), the EpSSG NRSTS 2005 study currently represents the benchmark for these tumors, establishing risk-adapted standards of care. The EpSSG has developed common treatment recommendations for the large group of adult-type NRSTS (including synovial sarcoma), and specific treatment recommendations for other particular adult-type histologies (ie, alveolar soft-part sarcoma, clear cell sarcoma and dermatofibrosarcoma protuberans); other highly malignant tumors with a biology and clinical behavior differing from those of adult-type NRSTS (ie, rhabdoid tumors and desmoplastic small round cell tumor); and soft tissue tumors of intermediate malignancy (ie desmoid-type fibromatosis, inflammatory myofibroblastic tumors, and infantile fibrosarcoma). New effective drugs are needed for patients whose NRSTS carries the worst prognosis, ie, those with unresectable tumors, metastases at diagnosis, or relapsing disease. Progress in this area relies on our ability to develop international integrated prospective collaborations, both within existing pediatric oncology networks and, importantly, between the communities of specialists treating pediatric and adult sarcoma.
PubMed: 36176694
DOI: 10.2147/CMAR.S368381 -
Journal of Clinical Oncology : Official... Sep 2021Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. Despite aggressive therapy, the 5-year survival rate for patients with metastatic or recurrent...
PURPOSE
Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. Despite aggressive therapy, the 5-year survival rate for patients with metastatic or recurrent disease remains poor, and beyond fusion status, no genomic markers are available for risk stratification. We present an international consortium study designed to determine the incidence of driver mutations and their association with clinical outcome.
PATIENTS AND METHODS
Tumor samples collected from patients enrolled on Children's Oncology Group trials (1998-2017) and UK patients enrolled on malignant mesenchymal tumor and RMS2005 (1995-2016) trials were subjected to custom-capture sequencing. Mutations, indels, gene deletions, and amplifications were identified, and survival analysis was performed.
RESULTS
DNA from 641 patients was suitable for analyses. A median of one mutation was found per tumor. In fusion-negative cases, mutation of any RAS pathway member was found in > 50% of cases, and 21% had no putative driver mutation identified. (15%), (15%), and (13%) mutations were found at a higher incidence than previously reported and mutations were associated with worse outcomes in both fusion-negative and fusion-positive cases. Interestingly, mutations in isoforms predominated in infants < 1 year (64% of cases). Mutation of was associated with histologic patterns beyond those previously described, older age, head and neck primary site, and a dismal survival. Finally, we provide a searchable companion database (ClinOmics), containing all genomic variants, and clinical annotation including survival data.
CONCLUSION
This is the largest genomic characterization of clinically annotated rhabdomyosarcoma tumors to date and provides prognostic genetic features that refine risk stratification and will be incorporated into prospective trials.
Topics: Adolescent; Adult; Biomarkers, Tumor; Child; Child, Preschool; DNA Mutational Analysis; Databases, Genetic; Disease Progression; Female; Gene Amplification; Gene Deletion; Gene Expression Profiling; Genetic Predisposition to Disease; Genomics; Humans; INDEL Mutation; Infant; Infant, Newborn; Male; Phenotype; Predictive Value of Tests; Progression-Free Survival; Rhabdomyosarcoma, Alveolar; Rhabdomyosarcoma, Embryonal; Risk Assessment; Risk Factors; Time Factors; Transcriptome; United Kingdom; United States; Young Adult
PubMed: 34166060
DOI: 10.1200/JCO.20.03060 -
Science Advances Feb 2023Rhabdomyosarcoma (RMS) is a group of pediatric cancers with features of developing skeletal muscle. The cellular hierarchy and mechanisms leading to developmental arrest...
Rhabdomyosarcoma (RMS) is a group of pediatric cancers with features of developing skeletal muscle. The cellular hierarchy and mechanisms leading to developmental arrest remain elusive. Here, we combined single-cell RNA sequencing, mass cytometry, and high-content imaging to resolve intratumoral heterogeneity of patient-derived primary RMS cultures. We show that the aggressive alveolar RMS (aRMS) subtype contains plastic muscle stem-like cells and cycling progenitors that drive tumor growth, and a subpopulation of differentiated cells that lost its proliferative potential and correlates with better outcomes. While chemotherapy eliminates cycling progenitors, it enriches aRMS for muscle stem-like cells. We screened for drugs hijacking aRMS toward clinically favorable subpopulations and identified a combination of RAF and MEK inhibitors that potently induces myogenic differentiation and inhibits tumor growth. Overall, our work provides insights into the developmental states underlying aRMS aggressiveness, chemoresistance, and progression and identifies the RAS pathway as a promising therapeutic target.
Topics: Child; Humans; Rhabdomyosarcoma, Alveolar; Rhabdomyosarcoma; Muscle, Skeletal; Cell Differentiation; Antineoplastic Agents; Cell Line, Tumor
PubMed: 36753540
DOI: 10.1126/sciadv.ade9238 -
European Journal of Cancer (Oxford,... Sep 2022Rhabdomyosarcomas (RMSs) are the most common soft tissue sarcomas in children/adolescents less than 18 years of age with an annual incidence of 1-2/million.... (Review)
Review
Molecular testing of rhabdomyosarcoma in clinical trials to improve risk stratification and outcome: A consensus view from European paediatric Soft tissue sarcoma Study Group, Children's Oncology Group and Cooperative Weichteilsarkom-Studiengruppe.
Rhabdomyosarcomas (RMSs) are the most common soft tissue sarcomas in children/adolescents less than 18 years of age with an annual incidence of 1-2/million. Inter/intra-tumour heterogeneity raise challenges in clinical, pathological and biological research studies. Risk stratification in European and North American clinical trials previously relied on clinico-pathological features, but now, incorporates PAX3/7-FOXO1-fusion gene status in the place of alveolar histology. International working groups propose a coordinated approach through the INternational Soft Tissue SaRcoma ConsorTium to evaluate the specific genetic abnormalities and generate and integrate molecular and clinical data related to patients with RMS across different trial settings. We review relevant data and present a consensus view on what molecular features should be assessed. In particular, we recommend the assessment of the MYOD1-LR122R mutation for risk escalation, as it has been associated with poor outcomes in spindle/sclerosing RMS and rare RMS with classic embryonal histopathology. The prospective analyses of rare fusion genes beyond PAX3/7-FOXO1 will generate new data linked to outcomes and assessment of TP53 mutations and CDK4 amplification may confirm their prognostic value. Pathogenic/likely pathogenic germline variants in TP53 and other cancer predisposition genes should also be assessed. DNA/RNA profiling of tumours at diagnosis/relapse and serial analyses of plasma samples is recommended where possible to validate potential molecular biomarkers, identify new biomarkers and assess how liquid biopsy analyses can have the greatest benefit. Together with the development of new molecularly-derived therapeutic strategies that we review, a synchronised international approach is expected to enhance progress towards improved treatment assignment, management and outcomes for patients with RMS.
Topics: Adolescent; Child; Consensus; Humans; Molecular Diagnostic Techniques; Neoplasm Recurrence, Local; Prospective Studies; Rhabdomyosarcoma; Rhabdomyosarcoma, Embryonal; Risk Assessment; Soft Tissue Neoplasms
PubMed: 35839732
DOI: 10.1016/j.ejca.2022.05.036 -
Oncoimmunology 2022Resistance remains an obstacle to anti-programmed cell death protein 1 (PD-1) therapy in human cancer. One critical resistance mechanism is the lack of T cell chemotaxis...
Resistance remains an obstacle to anti-programmed cell death protein 1 (PD-1) therapy in human cancer. One critical resistance mechanism is the lack of T cell chemotaxis in the tumor microenvironment (TME). CXCL10-CXCR3 signaling is required for T cell tumor infiltration and tumor immunotherapy. Oncolytic viruses (OVs), including oncolytic adenoviruses (AdVs), induce effective T cell immunity and tumor infiltration. Thus, arming OV with CXCL10 would be an attractive strategy to overcome resistance to anti-PD1 therapy. Here, we successfully constructed a novel recombinant oncolytic adenovirus encoding murine CXCL10, named Adv-CXCL10. Through intratumoural injection, the continuous expression of the functional chemokine CXCL10 in the TME is realized to recruit more CXCR3 T cells into the TME to kill tumor cells, and the recombinant adenovirus shows great power to 'fire up' the TME and enhance the antitumour efficiency of PD-1 antibodies.
Topics: Adenoviridae; Adenoviridae Infections; Animals; Chemokine CXCL10; Chemotaxis; Humans; Mice; Neoplasms; Oncolytic Viruses; Rhabdomyosarcoma, Alveolar; Tumor Microenvironment
PubMed: 36092638
DOI: 10.1080/2162402X.2022.2118210 -
Nature Communications Jul 2022Despite advances in multi-modal treatment approaches, clinical outcomes of patients suffering from PAX3-FOXO1 fusion oncogene-expressing alveolar rhabdomyosarcoma (ARMS)...
Despite advances in multi-modal treatment approaches, clinical outcomes of patients suffering from PAX3-FOXO1 fusion oncogene-expressing alveolar rhabdomyosarcoma (ARMS) remain dismal. Here we show that PAX3-FOXO1-expressing ARMS cells are sensitive to pharmacological ataxia telangiectasia and Rad3 related protein (ATR) inhibition. Expression of PAX3-FOXO1 in muscle progenitor cells is not only sufficient to increase sensitivity to ATR inhibition, but PAX3-FOXO1-expressing rhabdomyosarcoma cells also exhibit increased sensitivity to structurally diverse inhibitors of ATR. Mechanistically, ATR inhibition leads to replication stress exacerbation, decreased BRCA1 phosphorylation and reduced homologous recombination-mediated DNA repair pathway activity. Consequently, ATR inhibitor treatment increases sensitivity of ARMS cells to PARP1 inhibition in vitro, and combined treatment with ATR and PARP1 inhibitors induces complete regression of primary patient-derived ARMS xenografts in vivo. Lastly, a genome-wide CRISPR activation screen (CRISPRa) in combination with transcriptional analyses of ATR inhibitor resistant ARMS cells identifies the RAS-MAPK pathway and its targets, the FOS gene family, as inducers of resistance to ATR inhibition. Our findings provide a rationale for upcoming biomarker-driven clinical trials of ATR inhibitors in patients suffering from ARMS.
Topics: Ataxia Telangiectasia Mutated Proteins; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; Oncogene Proteins, Fusion; PAX3 Transcription Factor; Paired Box Transcription Factors; Rhabdomyosarcoma; Rhabdomyosarcoma, Alveolar; Rhabdomyosarcoma, Embryonal
PubMed: 35879366
DOI: 10.1038/s41467-022-32023-7 -
Cancers Nov 2023Rhabdomyosarcoma is a rare cancer arising in skeletal muscle that typically impacts children and young adults. It is a worldwide challenge in child health as treatment... (Review)
Review
Rhabdomyosarcoma is a rare cancer arising in skeletal muscle that typically impacts children and young adults. It is a worldwide challenge in child health as treatment outcomes for metastatic and recurrent disease still pose a major concern for both basic and clinical scientists. The treatment strategies for rhabdomyosarcoma include multi-agent chemotherapies after surgical resection with or without ionization radiotherapy. In this comprehensive review, we first provide a detailed clinical understanding of rhabdomyosarcoma including its classification and subtypes, diagnosis, and treatment strategies. Later, we focus on chemotherapy strategies for this childhood sarcoma and discuss the impact of three mechanisms that are involved in the chemotherapy response including apoptosis, macro-autophagy, and the unfolded protein response. Finally, we discuss in vivo mouse and zebrafish models and in vitro three-dimensional bioengineering models of rhabdomyosarcoma to screen future therapeutic approaches and promote muscle regeneration.
PubMed: 37958442
DOI: 10.3390/cancers15215269 -
Science Translational Medicine Jul 2022Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma (RMS) is an aggressive childhood...
Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma (RMS) is an aggressive childhood soft tissue sarcoma transformed by the pathognomonic Paired Box 3-Forkhead Box O1 (PAX3-FOXO1) fusion protein, which governs a core regulatory circuitry transcription factor network. Here, we show that the histone lysine demethylase 4B (KDM4B) is a therapeutic vulnerability for PAX3-FOXO1 RMS. Genetic and pharmacologic inhibition of KDM4B substantially delayed tumor growth. Suppression of KDM4 proteins inhibited the expression of core oncogenic transcription factors and caused epigenetic alterations of PAX3-FOXO1-governed superenhancers. Combining KDM4 inhibition with cytotoxic chemotherapy led to tumor regression in preclinical PAX3-FOXO1 RMS subcutaneous xenograft models. In summary, we identified a targetable mechanism required for maintenance of the PAX3-FOXO1-related transcription factor network, which may translate to a therapeutic approach for fusion-positive RMS.
Topics: Carcinogenesis; Cell Line, Tumor; Child; Forkhead Box Protein O1; Forkhead Transcription Factors; Gene Expression Regulation, Neoplastic; Humans; Jumonji Domain-Containing Histone Demethylases; Oncogene Proteins, Fusion; PAX3 Transcription Factor; Paired Box Transcription Factors; Rhabdomyosarcoma; Rhabdomyosarcoma, Alveolar
PubMed: 35857643
DOI: 10.1126/scitranslmed.abq2096