Ewing sarcoma (EWS) involves cell type specific activity of a gain of function chimeric transcriptional regulator has proven challenging to specifically target. 

We have exclusively focused on two fundamental approaches with the ultimate aim to deliver effective therapeutics for both primary and relapsed/refractory EWS cells. 

The first is selective EWS induced cell death that is independent of effects on other cell types. The second approach EWS neoantigen based immunological rejection of EWS cells.  To date, rare responders to signalling pathway EWS co-dependencies (e.g. IGF pathway) have resulted in rare complete regression and durable clinical responses, yet the biomarkers and range of mechanisms that might account for this unique EWS dependency have not been fully evaluated.

We have analysed material from a rare ES responder to linsitinib (dual IR/IGF1Ri) in a clinical trial and will report dependency on a neuronal transcription repressor gene siganture.

To evaluate whether fusion breakpoints generate EWS specific neoantigens, that can also be presented by MHC Class I and II, we have completed in silico prediction of breakpoint peptide high affinity MHC binding followed by TCR selection using naive donor invitro culture and peptide stimulation. 

We will report functional activity of resulting breakpoint neoantigen specific TCRs.  Revisiting questions in EWS with new approaches can reveal new mechanistic insights.