La Presentación Demuestra cómo éste fármaco mejora el índice terapéutico en comparación con trabectedina y suprime en mayor medida la actividad de EWSFLI1, una proteína oncogénica que tiene un papel crucial en el sarcoma de Ewing, una enfermedad huérfana con pocas opciones de tratamiento.El sarcoma de Ewing es un tumor pediátrico que se caracteriza por presentar una anomalía genética denominada traslocación (ruptura mecánica y la posterior reconexión de dos cromosomas diferentes). La traslocación tiene lugar entre los cromosomas 11 y 22 y se denomina t(11;22) o EWS/FLI1.
Actualmente, se sabe que las células de sarcoma de Ewing dependen del programa transcripcional de EWS/FL11 para su supervivencia, siendo un objetivo terapéutico suprimir la actividad de EWS/FL11. PM01183 ha demostrado este efecto, así como su sinergia con irinotecán para suprimir el crecimiento tumoral en esta enfermedad.
Además, el estudio confirma que PM01183 tiene un excelente perfil farmacológico, lo que sugiere que sus efectos pueden reproducirse en humanos. Todo ello, según los autores del estudio, pone de relieve que la traslación clínica de PM01183 como tratamiento dirigido específicamente a EWS/FL11, tanto en monoterapia como en combinación con irinotecán, está justificada.
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BACKGROUND:
Ewing sarcoma is a pediatric malignancy characterized by the fusion of the EWSR1 and FLI1 genes, which creates a constitutively activated transcription factor, EWS/FLI1. It is widely known that Ewing sarcoma cells depend on the transcriptional program of EWS/FLI1 for cell survival. Therefore, the goal of this research is to develop and clinically translate small molecules that suppress EWS/FLI1 activity. We have previously reported that the natural product trabectedin suppresses EWS/FLI1 activity. In addition, the compound synergizes with irinotecan to suppress Ewing sarcoma tumor growth. However, the compound suffers from a narrow therapeutic index that limits the poisoning of EWS/FLI1 in patients. In this report, we show that the trabectedin analog PM01183 has improved targeting of EWS/FLI1 and preserved synergy with irinotecan. In addition, the compound is known to have a dramatically improved therapeutic index suggesting improved activity of this compound in the clinic.
METHODS:
In this report, we characterize the mechanism of suppression of EWS/FLI1 by trabectedin using confocal immunocytochemistry and chromatin immunoprecipitation. We show enhanced suppression of EWS/FLI1 by PM01183 using the Fluidigm platform and confirm the results with a luciferase reporter construct and high-content quantitative PCR. Finally, we tested the ability of PM01183 to suppress tumor growth in xenograft models of Ewing sarcoma both in the absence and presence of irinotecan.
RESULTS:
PM01183 more effectively suppressed the gene signature of EWS/FLI1 than the parent compound trabectedin. In addition, the drug re-localizes EWS/FLI1 away from target genes in the nucleus leading to suppression of these EWS/FLI1 targets. These results are consistent with the activity of the parent compound, trabectedin, that blocks binding of EWS/FLI1 to chromatin. More importantly, the drug causes a regression of a TC32 xenograft and markedly suppresses growth of a TC71 xenograft when combined with irinotecan. Finally, PM01183 has a substantially improved pharmacologic profile in patients in comparison to trabectedin suggesting that these effects are bio-achievable in patients.
CONCLUSIONS:
In comparison to trabectedin, we have shown that its structural analog, PM01183 shows enhanced suppression of an EWS/FLI1 gene signature and preserves the synergy with irinotecan that we previously reported. We suggest a mechanistic basis for this activity against EWS/FLI1 and show excellent activity against Ewing sarcoma xenografts. Together, these results suggest that the clinical translation of PM01183 as an EWS/FLI1 targeted therapy both alone and in combination with irinotecan is warranted.