Eribulin regresses a doxorubicin‐resistant Ewing's sarcoma with a FUS‐ERG fusion and CDKN2A‐deletion in a patient‐derived orthotopic xenograft (PDOX) nude mouse model

Abstract

Ewing's sarcoma is a recalcitrant tumor greatly in need of more effective therapy. The aim of this study was to determine the efficacy of eribulin on a doxorubicin (DOX)-resistant Ewing's sarcoma patient derived orthotopic xenograft (PDOX) model. The Ewing's sarcoma PDOX model was previously established in the right chest wall of nude mice from tumor resected form the patient's right chest wall. In the previous study, the Ewing's sarcoma PDOX was resistant to doxorubicin (DOX) and sensitive to palbociclib and linsitinib. In the present study, the PDOX models were randomized into three groups when the tumor volume reached 60 mm 3 : G1, untreated control (n = 6); G2, DOX treated (n = 6), intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, Eribulin treated (n = 6, intravenous (i.v.) injection, weekly for 2 weeks).All mice were sacrificed on day 15. Changes in body weight and tumor volume were assessed two times per week. Tumor weight was measured after sacrifice. DOX did not suppress tumor growth compared to the control group (P = 0.589), consistent with the previous results in the patient and PDOX. Eribulin regressed tumor size significantly compared to G1 and G2 (P = 0.006, P = 0.017), respectively. No significant difference was observed in body weight among any group. Our results demonstrate that eribulin is a promising novel therapeutic agent for Ewing's sarcoma.

Combining Tumor-Selective Bacterial Therapy with <b><i>Salmonella typhimurium</i></b> A1-R and Cancer Metabolism Targeting with Oral Recombinant Methioninase Regressed an Ewing’s Sarcoma in a Patient-Derived Orthotopic Xenograft Model

“…We established PDOX models of all major cancer types [9-11, 14, 18-23, 27-31]. The PDOX model has great potential for precision personalized therapy of cancer.…”

“…Mouse housing, feeding, surgical processes, and imaging were conducted as previously described [9-11]. The mice were humanely sacrificed as previously described [9-11].…”

“…Mouse housing, feeding, surgical processes, and imaging were conducted as previously described [9-11]. The mice were humanely sacrificed as previously described [9-11]. All animal experiments were conducted with an AntiCancer Institutional Animal Care and Use Committee (IACUC) protocol specifically approved for this study and in accordance with the principles and procedures outlined in the National Institutes of Health Guide for the Care and Use of Animals under Assurance Number A3873-1.…”

“…Based on our PDOX results, an insulin-like growth factor-1 receptor inhibitor and irinotecan combined with temozolomide was clinically effective for this patient in different cycles of chemotherapy. We also observed that eribulin was effective on the ES PDOX [11]. …”

Recombinant methioninase combined with doxorubicin (DOX) regresses a DOX-resistant synovial sarcoma in a patient-derived orthotopic xenograft (PDOX) mouse model

“…Sarcoma is a group of 50 or more rare recalcitrant cancers [ 1 ]. In order to improve the outcome of sarcoma patients, we have developed patient-derived orthotopic xenograft (PDOX) models of the major sarcomas: soft-tissue sarcoma [ 2 – 4 ], follicular dendritic-cell sarcoma [ 5 ], Ewing’s sarcoma [ 6 – 10 ], undifferentiated pleomorphic soft-tissue sarcoma [ 11 , 12 ], osteosarcoma [ 13 – 16 , 25 ], rhabdomyosarcoma [ 17 , 18 ], leiomyosarcoma [ 19 ] and undifferentiated spindle-cell sarcoma (USCS) [ 20 , 23 , 26 ]. During the course of finding more efficacious agents for this group of diseases, we have found that our developmental therapeutic, recombinant methioninase (rMETase), is active and can inhibit or arrest tumor growth and in combination with an appropriate chemotherapy drug, can regress the PDOX tumors [ 7 , 21 – 26 ].…”