The combination of temozolomide-irinotecan regresses a doxorubicin-resistant patient-derived orthotopic xenograft (PDOX) nude-mouse model of recurrent Ewing’s sarcoma with a FUS-ERG fusion and CDKN2A deletion: Direction for third-line patient therapy
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Kentaro Miyake1,2,3, Takashi Murakami1,2,3, Tasuku Kiyuna1,2, Kentaro Igarashi1,2, Kei Kawaguchi1,2, Masuyo Miyake1,2,3, Yunfeng Li5, Scott D. Nelson5, Sarah M. Dry5, Michael Bouvet2, Irmina A. Elliott6, Tara A. Russell6, Arun S. Singh4, Mark A. Eckardt7, Yukihiko Hiroshima3, Masashi Momiyama3, Ryusei Matsuyama3, Takashi Chishima3, Itaru Endo3, Fritz C. Eilber6 and Robert M. Hoffman1,2
1AntiCancer Inc., San Diego, CA, USA
2Department of Surgery, University of California, San Diego, CA, USA
3Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
4Division of Hematology-Oncology, University of California, Los Angeles, CA, USA
5Department of Pathology, University of California, Los Angeles, CA, USA
6Division of Surgical Oncology, University of California, Los Angeles, CA, USA
7Department of Surgery, Yale School of Medicine, New Haven, CT, USA
Robert M. Hoffman, email: [email protected]
Fritz C. Eilber, email: [email protected]
Keywords: Ewing’s sarcoma, patient-derived orthotopic xenograft, irinotecan, temozolomide, third-line chemotherapy
Received: July 14, 2017 Accepted: July 23, 2017 Published: September 08, 2017
The aim of the present study was to determine the usefulness of a patient-derived orthotopic xenograft (PDOX) nude-mouse model of a doxorubicin-resistant metastatic Ewing’s sarcoma, with a unique combination of a FUS-ERG fusion and CDKN2A deletion, to identify effective drugs for third-line chemotherapy of the patient. Our previous study showed that cyclin-dependent kinase 4/6 (CDK4/6) and insulin-like growth factor-1 receptor (IGF-1R) inhibitors were effective on the Ewing’s sarcoma PDOX, but not doxorubicin, similar to the patient’s resistance to doxorubicin. The results of the previous PDOX study were successfully used for second-line therapy of the patiend. In the present study, the PDOX mice established with the Ewing’s sarcoma in the right chest wall were randomized into 5 groups when the tumor volume reached 60 mm3: untreated control; gemcitabine combined with docetaxel (intraperitoneal [i.p.] injection, weekly, for 2 weeks); irinotecan combined with temozolomide (irinotecan: i.p. injection; temozolomide: oral administration, daily, for 2 weeks); pazopanib (oral administration, daily, for 2 weeks); yondelis (intravenous injection, weekly, for 2 weeks). All mice were sacrificed on day 15. Body weight and tumor volume were assessed 2 times per week. Tumor weight was measured after sacrifice. Irinotecan combined with temozolomide was the most effective regimen compared to the untreated control group (p=0.022). Gemcitabine combined with docetaxel was also effective (p=0.026). Pazopanib and yondelis did not have significant efficacy compared to the untreated control (p=0.130, p=0.818). These results could be obtained within two months after the physician’s request and were used for third-line therapy of the patient.
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