Identification of Therapeutic Targets in Rhabdomyosarcoma through Integrated Genomic, Epigenomic, and Proteomic Analyses

Stewart, Elizabeth A.; McEvoy, Justina; Wang, Hong; Chen, Xiang; Honnell, Victoria; Ocarz, Monica; Gordon, Brittney; Dapper, Jason; Blankenship, Kaley; Yang, Yi-Yan; Li, Yuxin; Shaw, Timothy I.; Cho, Ji-Hoon; Wang, Xusheng; Xu, Beisi; Gupta, Pankaj; Fan, Yiping; Liu, Yu; Rusch, Michael; Griffiths, Lyra; Jeon, Jiehyun; Freeman, Burgess B.; Clay, Michael R.; Pappo, Alberto S.; Easton, John; Shurtleff, Sheila; Shelat, Anang A.; Zhou, Xin; Boggs, Kristy; Mulder, Heather L.; Yergeau, Donald; Bahrami, Armita; Mardis, Elaine R.; Wilson, Richard K.; Zhang, Jinghui; Peng, Junmin; Downing, James R.; Dyer, Michael A.

doi:10.1016/j.ccell.2018.07.012

Cited by 122 publications

(148 citation statements)

References 74 publications

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“…To gain insights into a possible role of DDX5 in RMS, we looked at its expression and epigenetic status through the Integrated Rhabdomyosarcoma database of the St. Jude Children's Research Hospital (https://pecan.stjude.cloud/proteinpaint/study/RHB2018) (14). Among the 18 chromatin hidden Markov modeling (chromHMM) states (15) identified in the study (14) (Supplemental Figure. 1A), DDX5 showed a strong active transcription start site (TSS) (red bars) and an actively transcribed gene body (green bars) in either normal myoblasts and myotubes, and primary ERMS and ARMS samples (Supplemental Figure 1B).…”

Section: Ddx5 Is Overexpressed In Rhabdomyosarcoma and Sustains Fp-armentioning

confidence: 99%

The RNA helicase DDX5 promotes alveolar rhabdomyosarcoma growth and survival

Gualtieri

Licursi

Mozzetta

2020

Preprint

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AbstractRhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood characterized by the inability to exit the proliferative myoblast-like stage. The alveolar fusion positive subtype (FP-ARMS) is the most aggressive and is mainly caused by the expression of PAX3/7-FOXO1 oncoproteins, which are challenging pharmacological targets. Thus, other therapeutic vulnerabilities resulting from gene expression changes are progressively being recognized. Here, we identified the DEAD box RNA helicase 5 (DDX5) as a potential therapeutic target to inhibit FP-ARMS growth. We show that DDX5 is overexpressed in alveolar RMS cells, demonstrating that its depletion drastically decreases FP-ARMS viability and slows tumor growth in xenograft models. Mechanistically, we provide evidence that DDX5 functions upstream the G9a/AKT survival signalling pathway, by modulating G9a protein stability. Finally, we show that G9a interacts with PAX3-FOXO1 and regulates its activity, thus sustaining FP-ARMS myoblastic state. Together, our findings identify a novel survival-promoting loop in FP-ARMS and highlight DDX5 as potential therapeutic target to arrest rhabdomyosarcoma growth.

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Section: Ddx5 Is Overexpressed In Rhabdomyosarcoma and Sustains Fp-armentioning

confidence: 99%

The RNA helicase DDX5 promotes alveolar rhabdomyosarcoma growth and survival

Gualtieri

Licursi

Mozzetta

2020

Preprint

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“…There are increasing numbers of studies analysing molecular changes in RMS, including proteome and epigenetic changes, and it has recently been found that ARMS occurs in more differentiated cells than ERMS, and that in RMS not only RAS /MEK/ERK/CDK4/6 pathway is deregulated, but there are also disorders in the so-called Unfolded Protein Response (pathway associated with the reaction to the accumulation of improperly folded proteins) and in mitosis between the G2 and M stage [68].…”

Section: Rhabdomyosarcomamentioning

confidence: 99%

Molecular biology of sarcoma

et al. 2019

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Soft tissue sarcomas are a large group of heterogenous neoplasms, many of them are highly aggressive. Most of the cases are sporadic, without any well-defined pathogenetic factor. Potential risk factors are ionizing radiation, lymphatic oedema (secondary angiosarcoma of the breast), viral infections (HHV8 and Kaposi sarcoma), exposure to chemical factors (vinyl chloride and hepatic angiosarcoma). Genetic susceptibility plays a role in a minority of cases. However, mutations in TP53, ATM and ATR genes are associated with enhanced susceptibility to radiation. Li-Fraumeni syndrome (autosomal dominant TP53 mutation) predisposes to development of malignancies, one third of them are sarcomas. Genetic alterations observed in sarcomas could be divided into three major groups characterized by: (1) chromosome translocations; (2) simple karyotype and mutations; (3) variably complex karyotypes. A large part of sarcomas belong to the first group and the specific chromosal translocations could be utilized in the diagnostic process. A smaller number of sarcomas could be assigned to the second group, e.g. desmoid fibromatosis (CTNNB1 or APC mutations) and GIST (KIT, PDGFRA, or less frequently BRAF, SDH, NF1). A large number of sarcomas are characterized by complex and variable karyotypes. Gene copy number alterations are frequent in this group, e.g. in well-differentiated liposarcoma there is an amplification of MDM2, CDK4 and HMGA2 genes or sarcoma-specific chromosomal break regions present in the CHOP gene in myxoid liposarcoma and FKHR in alveolar rhabdomyosarcoma.

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“…A recent preclinical study showed that combination of the Hsp90 inhibitor Ganetespib with Vincristine (VCR) and Irinotecan (IRN) significantly enhanced the tumor response in RMS xenograft models 43 . Considering that Ganetespib alone showed no significant effect on inhibition of RMS xenograft 43 while 17-DMAG significantly delayed tumor growth ( Fig.…”

Section: Combination Of 17-dmag With Conventional Chemotherapy or Bromentioning

confidence: 99%

Geldanamycin inhibits Jumonji histone lysine demethylase KDM4 and targets chimeric transcription factor PAX3-FOXO1

Abu‐Zaid

Singh

Lin

et al. 2019

Preprint

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Histone lysine demethylases (KDMs) are emerging as therapeutic targets in cancer. Development of potent KDM inhibitors may provide additional options for epigenomicsoriented therapies. Using a Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) functional demethylation assay, in combination with a high-content immunofluorescence imaging phenotypic screen, Matrix-Assisted Laser Desorption/Ionization-Fourier Transform Ion Cyclotron Resonance mass spectrometry (MALDI-FTICR MS) and Amplified Luminescent Proximity Homogeneous Assay (ALPHA), we identified geldanamycin, an inhibitor of heat shock protein 90 (Hsp90), as a novel inhibitor of JmjC-domain containing demethylases such as KDM4B. We further found that geldanamycin can destabilize the PAX3-FOXO1 fusion oncoprotein, an Hsp90 client, which is a driver of clinically unfavorable alveolar rhabdomyosarcoma (aRMS). We then hypothesized that dual inhibition of PAX3-FOXO1 and epigenetic modifiers of aRMS would have synergistic antitumor activity. We repurposed the geldanamycin analog 17-DMAG to target aRMS and found that 17-DMAG significantly delays tumor growth , extends survival in xenograft mouse models, and inhibits expression of PAX3-FOXO1 targets and multiple oncogenic pathways including MYC, E2F and NOTCH. In addition, the combination of 17-DMAG with conventional chemotherapy or the bromodomain inhibitor JQ1 significantly enhances therapeutic efficacy. In summary, we have identified geldanamycin and 17-DMAG as dual KDM/Hsp90 inhibitors and 17-DMAG is efficacious against PAX3-FOXO1-driven rhabdomyosarcoma.

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Identification of Therapeutic Targets in Rhabdomyosarcoma through Integrated Genomic, Epigenomic, and Proteomic Analyses

Cited by 122 publications

References 74 publications

The RNA helicase DDX5 promotes alveolar rhabdomyosarcoma growth and survival

The RNA helicase DDX5 promotes alveolar rhabdomyosarcoma growth and survival

Molecular biology of sarcoma

Geldanamycin inhibits Jumonji histone lysine demethylase KDM4 and targets chimeric transcription factor PAX3-FOXO1

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