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

Kentaro Miyake, Takashi Murakami, Tasuku Kiyuna, Kentaro Igarashi, Kei Kawaguchi, Masuyo Miyake, Yunfeng Li, Scott D. Nelson, Sarah M. Dry, Michael Bouvet, Irmina A. Elliott, Tara A. Russell, Arun S. Singh, Mark A. Eckardt, Yukihiko Hiroshima, Masashi Momiyama, Ryusei Matsuyama, Takashi Chishima, Itaru Endo, Fritz C. EilberRobert M. Hoffman

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

The aim of the present study was to determine the usefulness of a patientderived 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.

Original languageEnglish
Pages (from-to)103129-103136
Number of pages8
JournalOncotarget
Volume8
Issue number61
DOIs
Publication statusPublished - 2017 Jan 1
Externally publishedYes

Keywords

  • Combination
  • Ewing's sarcoma
  • Irinotecan
  • Patient-derived orthotopic xenograft
  • PDOX
  • Temozolomide
  • Third-line chemotherapy

ASJC Scopus subject areas

  • Oncology

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    Miyake, K., Murakami, T., Kiyuna, T., Igarashi, K., Kawaguchi, K., Miyake, M., Li, Y., Nelson, S. D., Dry, S. M., Bouvet, M., Elliott, I. A., Russell, T. A., Singh, A. S., Eckardt, M. A., Hiroshima, Y., Momiyama, M., Matsuyama, R., Chishima, T., Endo, I., ... Hoffman, R. M. (2017). 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. Oncotarget, 8(61), 103129-103136. https://doi.org/10.18632/oncotarget.20789