Insights into pediatric rhabdomyosarcoma research: Challenges and goals

Abstract

Overall survival rates for pediatric patients with high-risk or relapsed rhabdomyosarcoma (RMS) have not improved significantly since the 1980s. Recent studies have identified a number of targetable vulnerabilities in RMS, but these discoveries have infrequently translated into clinical trials. We propose streamlining the process by which agents are selected for clinical evaluation in RMS. We believe that strong consideration should be given to the development of combination therapies that add biologically targeted agents to conventional cytotoxic drugs. One example of this type of combination is the addition of the WEE1 inhibitor AZD1775 to the conventional cytotoxic chemotherapeutics, vincristine and irinotecan.

Keywords: cancer biology; early-phase clinical trials; genomics; rhabdomyosarcoma.

Figure 1

Histopathology and Genomics of the RMS subtypes Representative H&E staining (top), Circos plots (middle), and schematics of the genomic drivers (bottom) of each of the three RMS subtypes, PAX-fusion negative RMS, spindle cell/sclerosing RMS and PAX-fusion positive RMS. Histology courtesy of C.R. Antonescu. Circos plots adapted from ^,. In these plots, chromosomes 1–22 as well as the sex chromosomes are arrayed in a circle and arranged clockwise. The length of the chromosome in Mb is depicted outside each representation. Mutations for each tumor are indicated outside the chromosome number. Somatic single nucleotide variants (SNVs, blue), germline SNVs (gray), Tier 1 chromosomal translocations (translocations with strong clinical significance, green) and Tier 2 chromosomal translocations (translocations with potential clinical significance, orange) are shown. The outermost track of the Circos plot is a representation of the cytogenetic banding pattern of each chromosome, with the centromere colored red. For the spindle cell/sclerosing RMS tumor, somatic copy number alterations (aqua) are shown in the center track. In the innermost track, dots represent a somatic (blue) or germline (gray) SNV. The position of the dot within the track is representative of the variant allele frequency (VAF) for that SNV: SNVs with a higher VAF are positioned closer to the center of the Circos plot. In the center of the plot, lines link genes that are partners in Tier 1 (green) or Tier 2 (orange) translocations. In this figure, driver mutations for each RMS subtype are bolded (NRAS mutation, MYOD1 mutation and PAX3-FOXO1 translocation) are highlighted.