Metabolic targeting with recombinant methioninase combined with palbociclib regresses a doxorubicin-resistant dedifferentiated liposarcoma

Kentaro Igarashi, Kei Kawaguchi, Tasuku Kiyuna, Kentaro Miyake, Masuyo Miyaki, Norio Yamamoto, Katsuhiro Hayashi, Hiroaki Kimura, Shinji Miwa, Takashi Higuchi, Arun S. Singh, Bartosz Chmielowski, Scott D. Nelson, Tara A. Russell, Mark A. Eckardt, Sarah M. Dry, Yunfeng Li, Shree Ram Singh, Sant P. Chawla, Fritz C. EilberHiroyuki Tsuchiya, Robert M. Hoffman

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Liposarcoma is the most common type of soft tissue sarcoma. Among the subtypes of liposarcoma, dedifferentiated liposarcoma (DDLPS) is recalcitrant and has the lowest survival rate. The aim of the present study is to determine the efficacy of metabolic targeting with recombinant methioninase (rMETase) combined with palbociclib (PAL) against a doxorubicin (DOX)-resistant DDLPS in a patient-derived orthotopic xenograft (PDOX) model. A resected tumor from a patient with recurrent high-grade DDLPS in the right retroperitoneum was grown orthotopically in the right retroperitoneum of nude mice to establish a PDOX model. The PDOX models were randomized into the following groups when tumor volume reached 100 mm3: G1, control without treatment; G2, DOX; G3, PAL; G4, recombinant methioninase (rMETase); G5, PAL combined with rMETase. Tumor length and width were measured both pre- and post-treatment. On day 14 after initiation, all treatments significantly inhibited tumor growth compared to the untreated control except DOX. PAL combined with rMETase was significantly more effective than both DOX, rMETase alone, and PAL alone. Combining PAL and rMETase significantly regressed tumor volume on day 14 after initiation of treatment and was the only treatment to do so. The relative body weight on day 14 compared with day 0 did not significantly differ between each treatment group. The results of the present study indicate the powerful combination of rMETase and PAL should be tested clinically against DDLPS in the near future.

Original languageEnglish
Pages (from-to)912-917
Number of pages6
JournalBiochemical and biophysical research communications
Volume506
Issue number4
DOIs
Publication statusPublished - 2018 Dec 2

Keywords

  • Combination
  • Doxorubicin
  • Efficacy
  • Liposarcoma
  • Methioninase
  • PDOX
  • Palbociclib
  • Resistant
  • rMETase

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Igarashi, K., Kawaguchi, K., Kiyuna, T., Miyake, K., Miyaki, M., Yamamoto, N., Hayashi, K., Kimura, H., Miwa, S., Higuchi, T., Singh, A. S., Chmielowski, B., Nelson, S. D., Russell, T. A., Eckardt, M. A., Dry, S. M., Li, Y., Singh, S. R., Chawla, S. P., ... Hoffman, R. M. (2018). Metabolic targeting with recombinant methioninase combined with palbociclib regresses a doxorubicin-resistant dedifferentiated liposarcoma. Biochemical and biophysical research communications, 506(4), 912-917. https://doi.org/10.1016/j.bbrc.2018.10.119