Targeted Therapy–based Combination Treatment in Rhabdomyosarcoma

Erp, Anke van; Graaf, Winette T.A. van der; Fleuren, Emmy D.G.

doi:10.1158/1535-7163.mct-17-1131

Cited by 34 publications

(30 citation statements)

References 86 publications

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“…Survival in fusion gene-positive patients is extremely poor, with a 5-year overall survival of 7% in this cohort. Novel drugs are being investigated and may be applied, preferably in combination settings, based on preclinical research [32]. Unfortunately, the recent ARMS cohort of the CREATE study did not benefit from the ALK/MET inhibitor [33].…”

Section: Discussionmentioning

confidence: 99%

Embryonal and Alveolar Rhabdomyosarcoma in Adults: Real-Life Data From a Tertiary Sarcoma Centre

et al. 2020

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Aims: Embryonal and alveolar rhabdomyosarcoma (ERMS, ARMS) are subtypes of RMS that mainly occur in children, with relatively good outcomes. The incidence in adults is extremely low and survival is significantly worse compared with children. Data are scarce and literature generally combines all RMS subtypes, including pleomorphic RMS, which primarily occurs in adults and behaves more like undifferentiated pleomorphic sarcoma. The aim of this study was to evaluate patient and tumour characteristics, outcome and prognostic factors in adult patients with ERMS and ARMS. Materials and methods: All adult (18 years or older) ERMS and ARMS patients (presenting 1990e2016) were identified from a prospectively maintained database and were included in this analysis. Results: Overall, 66 patients were included (42 men, 24 women). The median age at presentation was 28 years (range 18e71). The median overall survival for all ARMS (n ¼ 42) and ERMS (n ¼ 24) patients was 18 months, with a 5-year overall survival rate of 27%. Patients presenting with localised disease (n ¼ 38, 58%) and metastatic disease (n ¼ 25, 42%), had a 5-year overall survival rate of 36% and 11%, respectively. In univariate analysis we found alveolar subtype, fusion gene positivity, infiltrative tumour and metastatic presentation to be negative prognostic factors. Conclusion: Survival in adult ERMS and ARMS patients is poor and the current data may be useful in the design of trials with novel agents. Ideally, paediatric and adult oncologists should set up trials together to get a better understanding of biological, genetic and clinically relevant factors in this disease.

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Section: Discussionmentioning

confidence: 99%

Embryonal and Alveolar Rhabdomyosarcoma in Adults: Real-Life Data From a Tertiary Sarcoma Centre

et al. 2020

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“…Further work to verify the discussed pathways as mediators of metastasis will be essential for targeted therapies against metastatic disease. Studies combining inhibition of PI3K/AKT pathway with inhibitors of other proteins that promote RMS metastasis (e.g., IGF1R or mTOR) are ongoing, with promising preclinical results showing synergism [143,144].…”

Section: Implications and Future Directionsmentioning

confidence: 99%

Signaling pathways in Rhabdomyosarcoma invasion and metastasis

Ramadan

Fahs

Ghayad

et al. 2020

Cancer Metastasis Rev

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Rhabdomyosarcoma (RMS) is an aggressive childhood mesenchymal tumor with two major molecular and histopathologic subtypes: fusion-positive (FP)RMS, characterized by the PAX3-FOXO1 fusion protein and largely of alveolar histology, and fusion-negative (FN)RMS, the majority of which exhibit embryonal tumor histology. Metastatic disease continues to be associated with poor overall survival despite intensive treatment strategies. Studies on RMS biology have provided some insight into autocrine as well as paracrine signaling pathways that contribute to invasion and metastatic propensity. Such pathways include those driven by the PAX3-FOXO1 fusion oncoprotein in FPRMS and signaling pathways such as IGF/RAS/MEK/ERK, PI3K/AKT/mTOR, cMET, FGFR4, and PDGFR in both FP and FNRMS. In addition, specific cytoskeletal proteins, G protein coupled receptors, Hedgehog, Notch, Wnt, Hippo, and p53 pathways play a role, as do specific microRNA. Paracrine factors, including secreted proteins and RMS-derived exosomes that carry cargo of protein and miRNA, have also recently emerged as potentially important players in RMS biology. This review summarizes the known factors contributing to RMS invasion and metastasis and their implications on identifying targets for treatment and a better understanding of metastatic RMS.

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“…Development of new mechanism-based drugs for treatment of RMS is ongoing and includes ROS-inducing anticancer agents, which have been identified in genomic studies and are effective tumor growth inhibitors in RMS patient-derived xenografts (14)(15)(16)(17)(18). The nuclear orphan receptor NR4A1 is overexpressed in tumors from patients with RMS and in other solid tumors (19)(20)(21)(22)(23)(24)(25)(26)(27), and studies in the laboratory have been investigating the functions of NR4A1 in RMS and solid tumor-derived cancer cell lines by RNAi (23)(24)(25)(27)(28)(29)(30)(31)(32).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of NR4A1 Promotes ROS Accumulation and IL24-Dependent Growth Arrest in Rhabdomyosarcoma

Hedrick

Mohankumar

Lacey

et al. 2019

Molecular Cancer Research

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Nuclear receptor 4A1 (NR4A1, Nur77) is overexpressed in rhabdomyosarcoma (RMS), and inactivation of NR4A1 (siNR4A1) or treatment with the NR4A1 antagonist 1,1-bis (3 0 -indoly)-1-(p-hydroxy-phenyl)methane (DIM-C-pPhOH) has antiproliferative and proapoptotic effects on RMS cells. However, the mechanism by which NR4A1 inhibition exerts these effects is poorly defined. Here, we report that NR4A1 silencing or inhibition resulted in accumulation of reactive oxygen species (ROS) and ROS-dependent induction of the tumor suppressor-like cytokine IL24 in RMS cells. Mechanistically, NR4A1 was found to regulate the expression of the proreductant genes thioredoxin domain-containing 5 (TXNDC5) and isocitrate dehydrogenase 1 (IDH1), which are downregulated in RMS cells following NR4A1 knockdown or inhibition. Silencing TXNDC5 and IDH1 also induced ROS accumulation and IL24 expression in RMS cells, suggesting that NR4A1 antagonists mediate their antiproliferative and apoptotic effects through modulation of proreductant gene expression. Finally, cotreatment with the antioxidant glutathione or IL24-blocking antibody reversed the effects of NR4A1 inhibition, demonstrating the importance of both ROS and IL24 in mediating the cellular responses.Implications: Overall, these data elucidate the mechanism by which NR4A1 inhibition functions to inhibit the proliferation, survival, and migration of RMS cells.

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Targeted Therapy–based Combination Treatment in Rhabdomyosarcoma

Cited by 34 publications

References 86 publications

Embryonal and Alveolar Rhabdomyosarcoma in Adults: Real-Life Data From a Tertiary Sarcoma Centre

Embryonal and Alveolar Rhabdomyosarcoma in Adults: Real-Life Data From a Tertiary Sarcoma Centre

Signaling pathways in Rhabdomyosarcoma invasion and metastasis

Inhibition of NR4A1 Promotes ROS Accumulation and IL24-Dependent Growth Arrest in Rhabdomyosarcoma

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