Whole Genome sequencing of Intraosseous spindle cell Rhabdomyosarcoma (IORMS)

Here we present comprehensive, multi-omic and functional analysis, to discover and preclinically validate novel actionable molecular targets for a rare case of intraosseus rhabdomyosarcoma with TFCP2-rearrangement. Whole genome sequencing analyses of matched patient tumour and xenograft material revealed alterations in gene networks associated with the oncogenic, potentially targetable PI3K/AKT pathway. Preclinical assessments revealed that targeting the pathway with a small molecule PI3K/mTOR inhibitor dactolisib presents a promising treatment approach for this rare cancer, decreasing cancer cell viability in vitro and significantly reducing tumour growth in vivo. Parallel identification of the codeletion of adjacent genes CDKN2A and MTAP in these tumours, led us to further explore PRMT5 inhibition as a potential therapeutic approach.