Identification of therapeutic targets in chordoma through comprehensive genomic and transcriptomic analyses

Abstract

Chordoma is a rare, orphan cancer arising from embryonal precursors of bone. Surgery and radiotherapy (RT) provide excellent local control, often at the price of significant morbidity due to the structures involved and the need for relatively high doses of RTare not typically curative; however, recurrence remains high. Although our understanding of the genetic changes that occur in chordoma is evolving rapidly, this knowledge has yet to translate into treatments. We performed comprehensive DNA (paired tumor/normal whole exome and shallow whole genome) and RNA (tumor whole transcriptome) next-generation sequencing analyses of archival sacral and clivus chordoma specimens. Incorporation of transcriptomic data enabled the identification of gene overexpression and expressed DNA alterations, and thus provided additional support for potential therapeutic targets. In three patients, we identified alterations that may be amenable to off-label FDA-approved treatments for other tumor types. These alterations include FGFR1 overexpression (ponatinib, pazopanib) and, copy number duplication of CDK4 (palbociclib) and ERBB3 (gefitinib), and V721G mutation of IGF1R (linsitinib, erlotinib). In a third patient, a missense mutation in IGF1R was identified, suggesting potential activity for investigational anti-IGF1R strategies. Lastly, in the fourth patient, no candidate treatment was identified. Ggermline DNA demonstrated predicted pathogenic changes in CHEK2 and ATM, which may have predisposed the patient to developing chordoma at a young age and may also be associated with potential sensitivity to PARP inhibitors due to homologous recombination repair deficiency. Our findings demonstrate that chordoma patients present with aberrations in overlapping pathways. These results provide support for targeting the IGF1R/FGFR/EGFR and CDK4/6 pathways as treatment strategies for chordoma patients. This study underscores the value of comprehensive genomic and transcriptomic analysis in the development of rational, individualized treatment plans for chordoma.