Recombinant methioninase (rMETase) is an effective therapeutic for BRAF-V600E-negative as well as -positive melanoma in patient-derived orthotopic xenograft (PDOX) mouse models

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

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Melanoma is a recalcitrant disease. Melanoma patients with the BRAF-V600E mutation have been treated with the drug vemurafenib (VEM) which targets this mutation. However, we previously showed that VEM is not very effective against a BRAF-V600E melanoma mutant in a patient-derived orthotopic xenograft (PDOX) model. In contrast, we demonstrated that recombinant methioninase (rMETase) which targets the general metabolic defect in cancer of methionine dependence, was effective against the BRAF-V600E mutant melanoma PDOX model. In the present study, we demonstrate that rMETase is effective against a BRAF-V600E-negative melanoma PDOX which we established. Forty BRAF-V600E-negative melanoma PDOX mouse models were randomized into four groups of 10 mice each: untreated control (n = 10); temozolomide (TEM) (25 mg/kg, p.o., 14 consecutive days, n = 10); rMETase (100 units, i.p., 14 consecutive days, n = 10); TEM + rMETase (TEM: 25 mg/kg, p.o., rMETase: 100 units, i.p., 14 consecutive days, n = 10). All treatments inhibited tumor growth compared to untreated control (TEM: p = 0.0003, rMETase: p = 0.0006, TEM/ rMETase: p = 0.0002) on day 14 after initiation. Combination therapy of TEM and rMETase was significantly more effective than either mono-therapy (TEM: p = 0.0113, rMETase: p = 0.0173). The present study shows that TEM combined with rMETase is effective for BRAF-V600E-negative melanoma PDOX similar to the BRAF-V600Epositive mutation melanoma. These results suggest rMETase in combination with firstline chemotherapy can be highly effective in both BRAF-V600E-negative as well as BRAF-V600E-positive melanoma and has clinical potential for this recalcitrant disease.

Original languageEnglish
Pages (from-to)915-923
Number of pages9
JournalOncotarget
Volume9
Issue number1
DOIs
Publication statusPublished - 2018

Keywords

  • BRAF-V600E mutation
  • Melanoma
  • Methionine dependence
  • PDOX
  • Recombinant methioninase

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Kawaguchi, K., Igarashi, K., Li, S., Han, Q., Tan, Y., Miyake, K., Kiyuna, T., Miyake, M., Murakami, T., Chmielowski, B., Nelson, S. D., Russell, T. A., Dry, S. M., Li, Y., Unno, M., Eilber, F. C., & Hoffman, R. M. (2018). Recombinant methioninase (rMETase) is an effective therapeutic for BRAF-V600E-negative as well as -positive melanoma in patient-derived orthotopic xenograft (PDOX) mouse models. Oncotarget, 9(1), 915-923. https://doi.org/10.18632/oncotarget.23185