Doxorubicin-resistant pleomorphic liposarcoma with PDGFRA gene amplification is targeted and regressed by pazopanib in a patient-derived orthotopic xenograft mouse model

Tasuku Kiyuna, Takashi Murakami, Yasunori Tome, Kentaro Igarashi, Kei Kawaguchi, Kentaro Miyake, Masuyo Miyake, Yunfeng Li, Scott D. Nelson, Sarah M. Dry, Arun S. Singh, Tara A. Russell, Shree Ram Singh, Fuminori Kanaya, Fritz C. Eilber, Robert M. Hoffman

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

Pleomorphic liposarcoma (PLPS) is a heterogeneous resistant group of tumors. Complete surgical resection is the only known way to treat PLPS. PLPS is reristant to both radiation and chemotherapy. Therefore, precise individualized therapy is needed to improve outcome of advanced PLPS patients. In this study, a patient-derived orthotopic xenograft (PDOX) model of a PDGFRA-amplified PLPS was established in the biceps femoris of nude mice by surgical orthotopic implantation (SOI) in order to match the patient. The PLPS PDOX was treated with pazopanib (PAZ) which targets PDGFRA, as well as with temozolomide (TEM) and first-line therapy doxorubicin (DOX). The PLPS PDOX was resistant to DOX and responded very well to PAZ as well as TEM. The tumor volume on treatment day-14 relative to day-1 was as follows: DOX (4.50 ± 2.6, p = 0.8087); PAZ (1.29 ± 0.9, p = 0.0008 compared to the control, p = 0.0167 compared to DOX); TEM (1.07 ± 0.8, p = 0.0079 compared to the control, p = 0.0079 compared to DOX). There was no significant difference in body weight between any treated group or control. The PAZ- and TEM-treated tumors showed extensive necrosis compared to the DOX-treated and untreated PDOX tumors. The present study showed that PDGFRA amplification could be effectively targeted by PAZ. The PLPS PDOX model also identified the efficacy of TEM which does not target PDGFRA, indicating that the PDOX model can identify effective targeted therapy as well as standard therapy and at the same time, identify ineffective drugs, even if they are first-line.

Original languageEnglish
Pages (from-to)30-36
Number of pages7
JournalTissue and Cell
Volume53
DOIs
Publication statusPublished - 2018 Aug
Externally publishedYes

Keywords

  • PDGFRA
  • PDOX
  • Pazopanib
  • Pleomorphic liposarcoma
  • Targeted therapy
  • Temozolomide

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology

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