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Rhabdomyosarcomas are aggressive pediatric soft‐tissue sarcomas and include high‐risk PAX3–FOXO1 fusion‐gene‐positive cases. Fibroblast growth factor receptor 4 (FGFR4) is known to contribute to rhabdomyosarcoma progression; here, we sought to investigate the involvement and potential for therapeutic targeting of other FGFRs in this disease. Cell‐based screening of FGFR inhibitors with potential for clinical repurposing (NVP‐BGJ398, nintedanib, dovitinib, and ponatinib) revealed greater sensitivity of fusion‐gene‐positive versus fusion‐gene‐negative rhabdomyosarcoma cell lines and was shown to be correlated with high expression of FGFR2 and its specific ligand, FGF7. Furthermore, patient samples exhibit higher mRNA levels of FGFR2 and FGF7 in fusion‐gene‐positive versus fusion‐gene‐negative rhabdomyosarcomas. Sustained intracellular mitogen‐activated protein kinase (MAPK) activity and FGF7 secretion into culture media during serum starvation of PAX3–FOXO1 rhabdomyosarcoma cells together with decreased cell viability after genetic silencing of FGFR2 or FGF7 was in keeping with a novel FGF7–FGFR2 autocrine loop. FGFR inhibition with NVP‐BGJ398 reduced viability and was synergistic with SN38, the active metabolite of irinotecan. In vivo, NVP‐BGJ398 abrogated xenograft growth and warrants further investigation in combination with irinotecan as a therapeutic strategy for fusion‐gene‐positive rhabdomyosarcomas. The PAX3‐FOXO1 fusion protein in high‐risk rhabdomyosarcomas increases FGFR4, FGFR2, and FGF7 levels. We demonstrate FGF7, a specific ligand of FGFR2, forms an autocrine loop that signals through MAPkinase and contributes to cell proliferation/survival. This is disrupted by the Receptor Tyrosine Kinase inhibitor (RTKi) NVP‐BGJ398, which also affects FGFR4. NVP‐BGJ398 combined with irinotecan shows potential to treat fusion‐positive rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is an aggressive soft tissue sarcoma with myogenic features affecting children and adolescents. The high-risk fusion-positive RMS subtype (FP-RMS), driven by the oncogenic chimeric transcription factor PAX3–FOXO1, shows 5-year overall survival not exceeding 30%. Here, we examine the impact of neddylation inhibition, a post-translational modification in which the NEDD8 peptide is conjugated to proteins, on the tumorigenic properties of FP-RMS. Here, we report that the NAE1 and UBA3 genes encoding the two subunits of the NEDD8-activating enzyme (NAE) heterodimer are upregulated in FP-RMS patients compared to healthy skeletal muscle tissues and highly expressed in RMS among several tumor types. Furthermore, DepMap analyses showed that FP-RMS cell lines are among the most sensitive to both NAE1 and UBA3 CRISPR-mediated knockout as well as to NAE pharmacological inhibition with MLN4924 compared to other cancer cell lines. In agreement, FP-RMS cells treated in vitro with MLN4924 (Pevonedistat) exhibited cell proliferation decrease, G2/M cell cycle arrest, senescence, and caspase- and PARP1-dependent apoptosis. These phenotypes were associated with increased γH2AX nuclear foci and protein levels, DNA double-strand breaks (DSB), and reduced RAD51 levels. NAE1 and UBA3 individual silencing mirrors the major effects of MLN4924. In addition, MLN4924 also prevented FP-RMS tumor growth in vivo. Combining MLN4924 with irradiation enhanced apoptosis and the inhibition of colony formation, cell cycle progression, and anchorage-independent and tumor spheroids growth compared to single treatments. Molecularly, MLN4924 amplified the irradiation-induced DNA damage by increasing γH2AX and DSBs, while reducing RAD51 expression and DNA-PKcs activation, both of which are involved in DNA repair. Collectively, our results suggest that the neddylation pathway is deregulated in FP-RMS, representing a potential therapeutic target. Therefore, MLN4924 could be considered as an anti-tumorigenic compound and a novel radiosensitizer in FP-RMS.

Our understanding of the molecular mechanisms underlying cancer development and evolution have evolved rapidly over recent years, and the variation from one patient to another is now widely recognized. Consequently, one-size-fits-all approaches to the treatment of cancer have been superseded by precision medicines that target specific disease characteristics, promising maximum clinical efficacy, minimal safety concerns, and reduced economic burden. While precision oncology has been very successful in the treatment of some tumors with specific characteristics, a large number of patients do not yet have access to precision medicines for their disease. The success of next-generation precision oncology depends on the discovery of new actionable disease characteristics, rapid, accurate, and comprehensive diagnosis of complex phenotypes within each patient, novel clinical trial designs with improved response rates, and worldwide access to novel targeted anticancer therapies for all patients. This review outlines some of the current technological trends, and highlights some of the complex multidisciplinary efforts that are underway to ensure that many more patients with cancer will be able to benefit from precision oncology in the near future.

The Frontline and Relapsed Rhabdomyosarcoma (FaR-RMS) clinical trial is an overarching, multinational study for children and adults with rhabdomyosarcoma (RMS). The trial, developed by the European Soft Tissue Sarcoma Study Group (EpSSG), incorporates multiple different research questions within a multistage design with a focus on (i) novel regimens for poor prognostic subgroups, (ii) optimal duration of maintenance chemotherapy, and (iii) optimal use of radiotherapy for local control and widespread metastatic disease. Additional sub-studies focusing on biological risk stratification, use of imaging modalities, including [18F]FDG PET-CT and diffusion-weighted MRI imaging (DWI) as prognostic markers, and impact of therapy on quality of life are described. This paper forms part of a Special Issue on rhabdomyosarcoma and outlines the study background, rationale for randomisations and sub-studies, design, and plans for utilisation and dissemination of results.

Rhabdomyosarcomas (RMS) are pediatric mesenchymal-derived malignancies encompassing PAX3/7-FOXO1 Fusion Positive (FP)-RMS, and Fusion Negative (FN)-RMS with frequent RAS pathway mutations. RMS express the master myogenic transcription factor MYOD that, whilst essential for survival, cannot support differentiation. Here we discover SKP2, an oncogenic E3-ubiquitin ligase, as a critical pro-tumorigenic driver in FN-RMS. We show that SKP2 is overexpressed in RMS through the binding of MYOD to an intronic enhancer. SKP2 in FN-RMS promotes cell cycle progression and prevents differentiation by directly targeting p27 Kip1 and p57 Kip2 , respectively. SKP2 depletion unlocks a partly MYOD-dependent myogenic transcriptional program and strongly affects stemness and tumorigenic features and prevents in vivo tumor growth. These effects are mirrored by the investigational NEDDylation inhibitor MLN4924. Results demonstrate a crucial crosstalk between transcriptional and post-translational mechanisms through the MYOD-SKP2 axis that contributes to tumorigenesis in FN-RMS. Finally, NEDDylation inhibition is identified as a potential therapeutic vulnerability in FN-RMS. SKP2 is an oncogenic E3-ubiquitin ligase. Here the authors show that SKP2 is epigenetically regulated by the muscle lineage transcription factor MYOD, supports tumorigenesis in the Fusion Negative (FN) subtype of rhabdomyosarcoma (RMS) and impairs differentiation promoting degradation of p57 Kip2 .

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and young people. Despite the advances in multimodality treatment over recent decades through successive prospective clinical trials, improved rates of survival for patients are mainly limited to those with localised RMS without adverse biologic features. Current clinicopathologic prognostic factors include PAX3(7)::FOXO1 fusion status, the site of primary disease, the pre-chemotherapy extent of disease (including microscopic vs. macroscopic residual disease, locoregional nodal involvement and metastatic status), tumour size and patient age. These factors are used to stratify patients into prognostic risk groups that guide treatment intensity and duration. Risk stratification algorithms are evolving, supported by advances in molecular biology and cancer genomics. In this review we focus on the poorest prognostic groups of paediatric-type RMS (i.e., Very High Risk or relapsed/progressive disease). These include patients whose tumours harbour poor biological characteristics such as PAX3(7)::FOXO1 fusion-positive tumours with locoregional nodal involvement and tumours harbouring other poor-risk genetic variants (particularly MYOD1 and TP53 variants); adolescent and young adult patients; newly diagnosed patients with metastatic RMS; and patients with relapsed and refractory disease. Here we aim to describe the clinical characteristics of these patients, outline current standard multimodality treatments in the context of sequential international clinical trials across the major cooperative groups and summarise emerging novel diagnostic and therapeutic approaches.

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