Rhabdomyosarcoma: Advances in Molecular and Cellular Biology

Sun, Xin; Guo, Wei; Shen, Jacson K.; Mankin, Henry J.; Hornicek, Francis J.; Duan, Zhenfeng

doi:10.1155/2015/232010

Cited by 79 publications

(97 citation statements)

References 98 publications

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“…There are two specific mutations of the FGFR4 kinase domain (K535 and E550) that causes autophosphorylation and constitutive activation. Such mutations have been identified in childhood rhabdomyosarcoma (RMS) (Helsten et al, 2015;Sun et al, 2015).…”

Section: Gene Mutationmentioning

confidence: 99%

FGFR a promising druggable target in cancer: Molecular biology and new drugs

Porta

Borea²,

Coelho³

et al. 2017

Critical Reviews in Oncology/Hematology

177

162

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Introduction The Fibroblast Growth Factor Receptor (FGFR) family consists of Tyrosine Kinase Receptors (TKR) involved in several biological functions. Recently, alterations of FGFR have been reported to be important for progression and development of several cancers. In this setting, different studies are trying to evaluate the efficacy of different therapies targeting FGFR. Areas Covered This review summarizes the current status of treatments targeting FGFR, focusing on the trials that are evaluating the FGFR profile as inclusion criteria: Multi-Target, Pan-FGFR Inhibitors and anti-FGF (Fibroblast Growth Factor)/FGFR Monoclonal Antibodies. Expert opinion Most of the TKR share intracellular signaling pathways; therefore, cancer cells tend to overcome the inhibition of one tyrosine kinase receptor by activating another. The future of TKI (Tyrosine Kinase Inhibitor) therapy will potentially come from multi-targeted TKIs that target different TKR simultaneously. It is crucial to understand the interaction of the FGF-FGFR axis with other known driver TKRs. Based on this, it is possible to develop therapeutic strategies targeting multiple connected TKRs at once. One correct step in this direction is the reassessment of multi target inhibitors considering the FGFR status of the tumor. Another opportunity arises from assessing the use of FGFR TKI on patients harboring FGFR alterations

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Section: Gene Mutationmentioning

confidence: 99%

FGFR a promising druggable target in cancer: Molecular biology and new drugs

Porta

Borea²,

Coelho³

et al. 2017

Critical Reviews in Oncology/Hematology

177

162

View full text Add to dashboard Cite

show abstract

“…RMS tumors are highly aggressive and typically develop from skeletal muscle cells arising in a variety of anatomic sites in the body 2,3 . There is a slightly higher prevalence of this disease in males than in females, and it is often associated with genetic disorders such as Li-Fraumeni familiar cancer syndrome and neurofibromatosis type 1 2 . Based on histologic criteria, RMS tumors are subdivided in two main groups, embryonal (ERMS) and alveolar (ARMS).…”

Section: Introductionmentioning

confidence: 99%

“…Based on histologic criteria, RMS tumors are subdivided in two main groups, embryonal (ERMS) and alveolar (ARMS). ERMS account for 60% of all RMS, affecting children under the age of 10, especially around the head and neck regions 2,3 . ARMS represent approximately 20% of all RMS, occurring mostly in adolescents, frequently localized in the limbs 3,4 .…”

Section: Introductionmentioning

confidence: 99%

Sequential combinations of chemotherapeutic agents with BH3 mimetics to treat rhabdomyosarcoma and avoid resistance

Alcon

Manzano-Muñoz

Prada

et al. 2020

Preprint

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Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood and adolescence. Refractory/relapsed RMS patients present a bad prognosis that combined with the lack of specific biomarkers difficult the development of new therapies. We here utilize dynamic BH3 Profiling (DBP), a functional predictive biomarker that measures net changes in mitochondrial apoptotic signaling, to identify anti-apoptotic adaptations upon treatment. We use this information to guide the use of BH3 mimetics to specifically inhibit BCL-2 prosurvival proteins, defeat resistance and avoid relapse to therapy. Indeed, we found that BH3 mimetics that selectively target BCL-xL and MCL-1 synergistically enhance the effect of the clinically used chemotherapeutic agents vincristine and doxorubicin in RMS cells. We validated this strategy in vivo using a RMS patient-derived xenograft (PDX) model and observed a reduction on tumor growth with a tendency to its stabilization with the sequential combination of vincristine and the MCL-1 inhibitor S63845. Finally, we identified the molecular mechanism by which RMS cells acquire resistance to vincristine: through the antiapoptotic protein MCL-1 for which we observed an enhanced binding between MCL-1 and BID after drug exposure, which is suppressed by the sequential addition of S63845. In conclusion, our findings validate the use of DBP as a functional assay to predict treatment effectiveness in RMS and provide a rationale for BH3 mimetic combination with chemotherapeutic agents to avoid tumor resistance, improve treatment efficiency and decrease undesired secondary effects. Alcon et al.

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“…sclerosing/spindle cell rhabdomyosarcoma (SRMS) in 2013 (5) . The two major histological subtypes of RMS are alveolar RMS, driven by the fusion protein PAX3-FKHR or PAX7-FKHR, and embryonic RMS, which is usually genetically heterogeneous (6) .…”

Section: Discussionmentioning

confidence: 99%