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High Efficacy of Recombinant Methioninase on Patient-Derived Orthotopic Xenograft (PDOX) Mouse Models of Cancer

  • Robert M. HoffmanEmail author
  • Takashi Murakami
  • Kei Kawaguchi
  • Kentaro Igarashi
  • Yuying Tan
  • Shukuan Li
  • Qinghong Han
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1866)

Abstract

Methionine (MET) is a general target in cancer due to the excess requirement of MET by cancer cells. MET has been effectively restricted by recombinant methioninase (rMETase) in mouse models of cell-line tumors. This chapter reviews the efficacy of rMETase on patient-derived orthotopic xenograft (PDOX) mouse models of human cancer. Ewing’s sarcoma is a recalcitrant disease even though development of multimodal therapy has improved patients’ outcome. A Ewing’s sarcoma was implanted in the right chest wall of nude mice to establish a PDOX model. rMETase effectively reduced tumor growth compared to the untreated control. The MET level both of plasma and supernatants derived from sonicated tumors was lower in the rMETase treatment group. Body weight did not significantly differ at any time points between the two groups. A PDOX nude mouse model of a BRAF V600E-mutant melanoma was established in the chest wall of nude mice and also tested with rMETase in combination with a first-line melanoma drug, temozolomide (TEM). Combination therapy of TEM and rMETase was significantly more efficacious than either monotherapy. The results reviewed in this chapter demonstrate the clinical potential of rMETase.

Key words

Methionine dependence Patient-derived orthotopic xenograft PDOX Recombinant methioninase rMETase Chemotherapy Combination 

References

  1. 1.
    Hoffman RM (2015) Development of recombinant methioninase to target the general cancer-specific metabolic defect of methionine dependence: a 40-year odyssey. Expert Opin Biol Ther 15:21–31CrossRefGoogle Scholar
  2. 2.
    Stern PH, Mecham JO, Wallace CD, Hoffman RM (1983) Reduced free-methionine in methionine-dependent SV40-transformed human fibroblasts synthesizing apparently normal amounts of methionine. J Cell Physiol 117:9–14CrossRefGoogle Scholar
  3. 3.
    Stern PH, Wallace CD, Hoffman RM (1984) Altered methionine metabolism occurs in all members of a set of diverse human tumor cell lines. J Cell Physiol 119:29–34CrossRefGoogle Scholar
  4. 4.
    Stern PH, Hoffman RM (1984) Elevated overall rates of transmethylation in cell lines from diverse human tumors. In Vitro 20:663–670CrossRefGoogle Scholar
  5. 5.
    Coalson DW, Mecham JO, Stern PH, Hoffman RM (1982) Reduced availability of endogenously synthesized methionine for S-adenosylmethionine formation in methionine dependent cancer cells. Proc Natl Acad Sci U S A 79:4248–4251CrossRefGoogle Scholar
  6. 6.
    Hoffman RM (2017) The wayward methyl group and the cascade to cancer. Cell Cycle 16:825–829CrossRefGoogle Scholar
  7. 7.
    Hoffman RM (2017) Is DNA methylation the new guardian of genome? Mol Cytogenetics 10:11CrossRefGoogle Scholar
  8. 8.
    Xu W, Gao L, Shao A, Zheng J, Zhang J (2017) The performance of [11C]-methionine PET in the differential diagnosis of glioma recurrence. Oncotarget 8:91030–91039PubMedPubMedCentralGoogle Scholar
  9. 9.
    Kawaguchi K, Igarashi K, Li S, Han Q, Tan Y, Kiyuna T, Miyake Y, Murakami T, Chmielowski B, Nelson SD, Russell TA, Dry SM, Li Y, Unno M, Eilber FC, Hoffman RM (2017) Combination treatment with recombinant methioninase enables temozolomide to arrest a BRAF V600E melanoma growth in a patient-derived orthotopic xenograft. Oncotarget 8:85516–85525PubMedPubMedCentralGoogle Scholar
  10. 10.
    Murakami T, Singh AS, Kiyuna T, Dry SM, Li Y, James AW, Igarashi K, Kawaguchi K, DeLong JC, Zhang Y, Hiroshima Y, Russell T, Eckardt MA, Yanagawa J, Federman N, Matsuyama R, Chishima T, Tanaka K, Bouvet M, Endo I, Eilber FC, Hoffman RM (2016) Effective molecular targeting of CDK4/6 and IGF-1R in a rare FUS-ERG fusion CDKN2A-deletion doxorubicin-resistant Ewing’s sarcoma in a patient-derived orthotopic xenograft (PDOX) nude-mouse model. Oncotarget 7:47556–47564PubMedPubMedCentralGoogle Scholar
  11. 11.
    Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C et al (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364:2507–2516CrossRefGoogle Scholar
  12. 12.
    Flaherty LE, Othus M, Atkins MB, Tuthill RJ, Thompson JA, Vetto JT, Haluska FG, Pappo AS, Sosman JA, Redman BG, Moon J, Ribas A, Kirkwood JM, Sondak VK (2014) Southwest Oncology Group S0008: a phase III trial of high-dose interferon Alfa-2b versus cisplatin, vinblastine, and dacarbazine, plus interleukin-2 and interferon in patients with high-risk melanoma--an intergroup study of cancer and leukemia Group B, Children’s Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. J Clin Oncol 32:3771–3778CrossRefGoogle Scholar
  13. 13.
    Tang H, Wang Y, Chlewicki LK, Zhang Y, Guo J, Liang W, Wang J, Wang X, Fu YX (2016) Facilitating T Cell infiltration in tumor microenvironment overcomes resistance to PD-L1 blockade. Cancer Cell 29:285–296CrossRefGoogle Scholar
  14. 14.
    Brozyna AA, Jóźwicki W, Roszkowski K, Filipiak J, Slominski AT (2016) Melanin content in melanoma metastases affects the outcome of radiotherapy. Oncotarget 7:17844–17853PubMedPubMedCentralGoogle Scholar
  15. 15.
    Slominski AT, Carlson JA (2014) Melanoma resistance: a bright future for academicians and a challenge for patient advocates. Mayo Clin Proc 89:429–433CrossRefGoogle Scholar
  16. 16.
    Kreis W, Hession C (1973) Isolation and purification of L-methionine-alpha-deamino-gamma-mercaptomethane-lyase (L-methioninase) from Clostridium sporogenes. Cancer Res 33:1862–1865PubMedGoogle Scholar
  17. 17.
    Tan Y, Sun X, Xu M, Tan X-Z, Sasson A, Rashidi B, Han Q, Tan X-Y, Wang X, An Z, Sun F-X, Hoffman RM (1999) Efficacy of recombinant methioninase in combination with cisplatin on human colon tumors in nude mice. Clin Cancer Res 5:2157–2163PubMedGoogle Scholar
  18. 18.
    Kokkinakis DM, Hoffman RM, Frenkel EP, Wick JB, Han Q, Xu M, Tan Y, Schold SC (2001) Synergy between methionine stress and chemotherapy in the treatment of brain tumor xenografts in athymic mice. Cancer Res 61:4017–4023PubMedGoogle Scholar
  19. 19.
    Mecham JO, Rowitch D, Wallace CD, Stern PH, Hoffman RM (1983) The metabolic defect of methionine dependence occurs frequently in human tumor cell lines. Biochem Biophys Res Commun 117:429–434CrossRefGoogle Scholar
  20. 20.
    Yoshioka T, Wada T, Uchida N, Maki H, Yoshida H, Ide N, Kasai H, Hojo K, Shono K, Maekawa R, Yagi S, Hoffman RM, Sugita K (1998) Anticancer efficacy in vivo and in vitro, synergy with 5-fluorouracil, and safety of recombinant methioninase. Cancer Res 58:2583–2587PubMedGoogle Scholar
  21. 21.
    Murakami T, Li S, Han Q, Tan Y, Kiyuna T, Igarashi K, Kawaguchi K, Hwang HK, Miyaki K, Singh AS, Nelson SD, Dry SM, Li Y, Hiroshima Y, Lwin TM, DeLong JC, Chishima T, Tanaka K, Bouvet M, Endo I, Eilber FC, Hoffman RM (2017) Recombinant methioninase effectively targets a Ewing’s sarcoma in a patient-derived orthotopic xenograft (PDOX) nude-mouse model. Oncotarget 8:35630–35638PubMedPubMedCentralGoogle Scholar
  22. 22.
    Kawaguchi K, Murakami T, Chmielowski B, Igarashi K, Kiyuna T, Unno M, Nelson SD, Russell TA, Dry SM, Li Y, Eilber FC, Hoffman RM (2016) Vemurafenib-resistant BRAF-V600E mutated melanoma is regressed by MEK targeting drug trametinib, but not cobimetinib in a patient-derived orthotopic xenograft (PDOX) mouse model. Oncotarget 7:71737–71743PubMedPubMedCentralGoogle Scholar
  23. 23.
    Kawaguchi K, Igarashi K, Murakami T, Chmiewloski B, Kiyuna T, Zhao M, Zhang Y, Singh A, Unno M, Nelson SD, Russell T, Dry SM, Li Y et al (2016) Tumor-targeting Salmonella typhimurium A1-R combined with temozolomide regresses malignant melanoma with a BRAF-V600 mutation in a patient-derived orthotopic xenograft (PDOX) model. Oncotarget 7:85929–85936PubMedPubMedCentralGoogle Scholar
  24. 24.
    Kawaguchi K, Igarashi K, Murakami T, Zhao M, Zhang Y, Chmielowski B, Kiyuna T, Nelson SD, Russell TA, Dry SM, Li Y, Unno M, Eilber FC, Hoffman RM (2017) Tumor-targeting Salmonella typhimurium A1-R sensitizes melanoma with a BRAF-V600E mutation to vemurafenib in a patient-derived orthotopic xenograft (PDOX) nude mouse model. J Cell Biochem 118:2314–2319CrossRefGoogle Scholar
  25. 25.
    Tan Y, Xu M, Tan XZ, Tan XY, Wang X, Saikawa Y, Nagahama T, Sun X, Lenz M, Hoffman RM (1997) Overexpression and large-scale production of recombinant L-methionine-α-deamino-γ-mercaptomethane-lyase for novel anticancer therapy. Protein Expr Purif 9:233–245CrossRefGoogle Scholar
  26. 26.
    Sun X, Tan Y, Yang Z, Li S, Hoffman RM (2005) A rapid HPLC method for the measurement of ultra-low plasma methionine concentrations applicable to methionine depletion therapy. Anticancer Res 24:59–62Google Scholar
  27. 27.
    Sugimura T, Birnbaum SM, Winitz M, Greenstein JP (1959) Quantitative nutritional studies with water-soluble, chemically defined diets. VIII. The forced feeding of diets each lacking in one essential amino acid. Arch Biochem Biophys 81:448–455CrossRefGoogle Scholar
  28. 28.
    Chello PL, Bertino JR (1973) Dependence of 5-methyltetrahydrofolate utilization by L5178Y murine leukemia cells in vitro on the presence of hydroxycobalamin and transcobalamin II. Cancer Res 33:1898–1904PubMedGoogle Scholar
  29. 29.
    Tan Y, Xu M, Hoffman RM (2010) Broad selective efficacy of recombinant methioninase and polyethylene glycol-modified recombinant methioninase on cancer cells in vitro. Anticancer Res 30:1041–1046PubMedGoogle Scholar
  30. 30.
    Guo HY, Herrera H, Groce A, Hoffman RM (1993) Expression of the biochemical defect of methionine dependence in fresh patient tumors in primary histoculture. Cancer Res 53:2479–2483PubMedGoogle Scholar
  31. 31.
    Guo H, Lishko VK, Herrera H, Groce A, Kubota T, Hoffman RM (1993) Therapeutic tumor-specific cell cycle block induced by methionine starvation in vivo. Cancer Res 53:5676–5679PubMedGoogle Scholar
  32. 32.
    Hoffman RM, Jacobsen SJ (1980) Reversible growth arrest in simian virus 40-transformed human fibroblasts. Proc Natl Acad Sci U S A 77:7306–7310CrossRefGoogle Scholar
  33. 33.
    Yano S, Li S, Han Q, Tan Y, Bouvet M, Fujiwara T, Hoffman RM (2014) Selective methioninase-induced trap of cancer cells in S/G2 phase visualized by FUCCI imaging confers chemosensitivity. Oncotarget 5:8729–8736CrossRefGoogle Scholar
  34. 34.
    Yano S, Takehara K, Zhao M, Tan Y, Han Q, Li S, Bouvet M, Fujiwara T, Hoffman RM (2016) Tumor-specific cell-cycle decoy by Salmonella typhimurium A1-R combined with tumor-selective cell-cycle trap by methioninase overcome tumor intrinsic chemoresistance as visualized by FUCCI imaging. Cell Cycle 15:1715–1723CrossRefGoogle Scholar
  35. 35.
    Borriello A, Della Ragione F (2017) The new anticancer era: tumor metabolism targeting. Cell Cycle 16:310–311CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Robert M. Hoffman
    • 1
    • 2
    Email author
  • Takashi Murakami
    • 1
    • 2
  • Kei Kawaguchi
    • 1
    • 2
  • Kentaro Igarashi
    • 1
    • 2
  • Yuying Tan
    • 1
  • Shukuan Li
    • 1
  • Qinghong Han
    • 1
  1. 1.AntiCancer, Inc.San DiegoUSA
  2. 2.Department of SurgeryUniversity of CaliforniaSan DiegoUSA

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