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Multi-Omic Analysis of Rhabdomyosarcoma Points to Drug Targets in Deregulated Pathways

NEW YORK (GenomeWeb) – A team led by researchers at St. Jude Children's Research Hospital has conducted an integrated analysis of rhabdomyosarcoma (RMS) samples that involved transcriptomic, epigenomic, proteomic, and phosphoproteomic data, leading them to a number of deregulated pathways.

Through subsequent preclinical testing, the researchers also found the WEE1 kinase to be a promising target for treating high-risk RMS.

The study, which is part of the St. Jude-Washington University Pediatric Cancer Genomic Project and was led by senior author Michael Dyer, chair of the Department of Developmental Neurobiology at St. Jude's, was published in Cancer Cell today.

"This research offers a template for exploring the origins and vulnerabilities of solid tumors by looking not only at somatic mutations, but also at epigenetic changes and ultimately differences in how those changes are manifest in protein expression and activity," Dyer said in a statement, adding that it "also highlights how preclinical models and extensive preclinical testing can help prioritize and streamline drug development."

Rhabdomyosarcoma, a childhood solid tumor that involves muscle and soft tissue, affects about 350 patients in the US each year. While the cure rate is 75 percent for patients with localized tumors, survival is only 30 percent for patient with metastatic disease and just 17 percent for those with recurring disease, and survival numbers have not improved much in the last 15 years. The majority of RMS cases are embryonal, or ERMS, while most others are of the alveolar (ARMS) type.

For their study, the researchers focused on 17 so-called orthotopic patient-derived xenografts (O-PDX) of pediatric solid tumors that had previously been studied at the genomic level, as well as on primary human myoblasts, myotubes, and fetal skeletal muscle samples. Specifically, they performed whole-genome bisulfite sequencing, RNA sequencing, and chromatin immunoprecipitation and sequencing (ChIP-seq).

In addition, they used 10-plex isobaric labeling mass spectrometry to quantify the proteome and phosphoproteome of 12 O-PDXs and several human myoblasts and myotubes in replicated experiments. In total, they analyzed more than 16,500 human proteins and almost 63,000 phosphorylation events on about 7,200 proteins.

They then analyzed the data across multiple platforms, using two approaches. In one, they looked at differentially expressed proteins and mRNAs in tumors and myoblasts and performed co-expression clustering of those genes and proteins that were conserved across the two platforms. For the other, they integrated transcriptomic, epigenomic, proteomic, and phosphoproteomic data with order statistics.

Their analyses showed that the RAS pathway, the unfolded protein response pathway, and the G2/M-mitotic spindle checkpoint pathway were the most affected pathways in the RMS samples.

Through extensive preclinical testing, which involved screening more than 1,700 drug-tumor combinations, they found that AZD1775, which inhibits the WEE1 enzyme in the G2/M pathway, shows promise as a treatment for high-risk RMS.

As a result, the Children's Oncology Group has expanded a multicenter phase I/II clinical trial of AZD1775 and the drug irinotecan to include high-risk rhabdomyosarcoma patients, according to St. Jude.

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