Individualized doxorubicin sensitivity testing of undifferentiated soft tissue sarcoma (USTS) in a patient-derived orthotopic xenograft (PDOX) model demonstrates large differences between patients

Kei Kawaguchi, Kentaro Igarashi, Tasuku Kiyuna, Kentaro Miyake, Masuyo Miyake, Takashi Murakami, Bartosz Chmielowski, Scott D. Nelson, Tara A. Russell, Sarah M. Dry, Yunfeng Li, Arun S. Singh, Michiaki Unno, Fritz C. Eilber, Robert M. Hoffman

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Doxorubicin (DOX) is often first-line treatment of undifferentiated/unclassified soft tissue sarcoma (USTS). However, the DOX response rate for USTS patients is low. Individualized precision-medicine technology that could identify DOX responders as well as non-responders would be of high value to cancer patients. In the present study, we established 5 patient-derived orthotopic xenograft (PDOX) nude mouse models from 5 USTS patients and evaluated the efficacy of DOX in each PDOX model. USTS's were grown orthotopically in the right thigh of nude mice to establish the PDOX models. Two weeks after implantation, the mouse models were randomized into two groups of 8 mice each: untreated control; and DOX (3 mg/kg, i.p., once a week for 2 weeks). DOX showed significant growth inhibition in only 2 USTS PDOX models out of 5 (p = 0.0054, p = 0.0055, respectively) on day 14 after initiation. DOX was ineffective in the other 3 PDOX models. However, even in the DOX-sensitive cases, DOX could not regress the PDOX tumors responding to treatment. The present study has important implications since this is the first in vivo study to compare the DOX sensitivity for USTS on multiple patient tumors. We showed that only two of five USTS were responsive to DOX, despite DOX being first line chemotherapy for USTS. The 3 resistant cases should not be treated with DOX clinically, in order to spare the patients' unnecessary toxicity. This PDOX model is useful for precise individualized drug sensitivity testing, especially for rare heterogeneous recalcitrant sarcomas such as USTS.

Original languageEnglish
Pages (from-to)627-633
Number of pages7
JournalCell Cycle
Volume17
Issue number5
DOIs
Publication statusPublished - 2018 Mar 4

Keywords

  • PDOX
  • Soft tissue sarcoma (STS)
  • doxorubicin
  • drug-response
  • individualized therapy
  • nude mice
  • precision therapy
  • undifferentiated/unclassified soft tissue sarcoma (USTS)

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Individualized doxorubicin sensitivity testing of undifferentiated soft tissue sarcoma (USTS) in a patient-derived orthotopic xenograft (PDOX) model demonstrates large differences between patients'. Together they form a unique fingerprint.

  • Cite this

    Kawaguchi, K., Igarashi, K., Kiyuna, T., Miyake, K., Miyake, M., Murakami, T., Chmielowski, B., Nelson, S. D., Russell, T. A., Dry, S. M., Li, Y., Singh, A. S., Unno, M., Eilber, F. C., & Hoffman, R. M. (2018). Individualized doxorubicin sensitivity testing of undifferentiated soft tissue sarcoma (USTS) in a patient-derived orthotopic xenograft (PDOX) model demonstrates large differences between patients. Cell Cycle, 17(5), 627-633. https://doi.org/10.1080/15384101.2017.1421876