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The Role of Temozolomide-Irinotecan in Doxorubicin- Resistant Cell Lines of Recurrent Ewing’s Sarcoma, in A Patient Derived Orthotopic Xenograft (PDOX) with EWS-ERG Fusion and CDKN2A Loss: What Impact the Combination has in Real Life Practice?

Introduction: A patient-derived orthotopic xenograft (PDOX) nude-mouse model and irrespective of genetic profile can help guiding our treatment in progressive and resistant Ewing Sarcoma (ES) patients progressed after Doxorubicin containing regimens. Patients and methods: In our study, the PDOX mice established model with ES were divided into two arms once tumor mass exceeded 60 mm3: (1) untreated control (2) irinotecan plus temozolomide (irinotecan: intra-peritoneal injection; temozolomide: orally, daily for 14 days). A similar study was carried out on patients from whom the graft was taken. We have collected data from 35 patients of ES: diagnosed, treated and progressed after the first line chemotherapy. Those patients received oral temozolomide 100mg/m2 on days 1 through 5 plus IV irinotecan 10-20 mg/m2/day on days 1 through 5 and day 8 through 12 (repeated every 3-4 weeks). results: Irinotecan plus temozolomide was found to be an effective combination when compared to the untreated control (p = 0.022) in mice model where tumor shrinkage was observed on day 10. To assure these findings, we have conducted in part, a study employing both Temozolomide and irinotecan in patients resistant to Doxorubicin containing regimens and demonstrating EWS-ERG fusion and CDKN2A loss. However, the same protocol was used to the same patient where the graft was taken showing not complete concordance between the lab and real practice. conclusion: PDOX is a good model to test a library of drugs on. It shows to be a promising method in several studies and in ours as well. Studies demonstrated that the combination of temozolomide/irrinotecan is effective in ES patients in progression after Doxorubicin resistance. KEYWOrDs: Ewing Sarcoma; Xenograft; Progression; ERG; EWS; CDKN2A