Efficacy of Recombinant Methioninase (rMETase) on Recalcitrant Cancer Patient-Derived Orthotopic Xenograft (PDOX) Mouse Models: A Review

Kawaguchi, Koji; Han, Qinghong; Li, Shukuan; Tan, Yuying; Igarashi, Kentaro; Murakami, Takashi; Unno, Michiaki; Hoffman, Robert M.

doi:10.3390/cells8050410

Cited by 38 publications

(28 citation statements)

References 74 publications

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“…The gene was derived from Pseudomonas putida and encodes L-methionine-γ-deamino-α-mercaptomethane-lyase, but is usually referred to as methioninase (METase). METase injection showed efficacy in both cell-based and patient derived xenograft (PDX) models of various cancers [69,[75][76][77][78][79]. Pilot phase 1 trials administered METase infusions to terminal cancer patients, which had no side effects even though a dramatic reduction of plasma methionine by 200-fold was achieved [59,80,81].…”

Section: Methionine Metabolism and Tumor Growthmentioning

confidence: 99%

Methionine Dependence of Cancer

2020

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Tumorigenesis is accompanied by the reprogramming of cellular metabolism. The shift from oxidative phosphorylation to predominantly glycolytic pathways to support rapid growth is well known and is often referred to as the Warburg effect. However, other metabolic changes and acquired needs that distinguish cancer cells from normal cells have also been discovered. The dependence of cancer cells on exogenous methionine is one of them and is known as methionine dependence or the Hoffman effect. This phenomenon describes the inability of cancer cells to proliferate when methionine is replaced with its metabolic precursor, homocysteine, while proliferation of non-tumor cells is unaffected by these conditions. Surprisingly, cancer cells can readily synthesize methionine from homocysteine, so their dependency on exogenous methionine reflects a general need for altered metabolic flux through pathways linked to methionine. In this review, an overview of the field will be provided and recent discoveries will be discussed.

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Section: Methionine Metabolism and Tumor Growthmentioning

confidence: 99%

Methionine Dependence of Cancer

2020

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“…These results suggest the use of a higher dose of methioninase and combination with chemotherapy to further control loco-regional recurrence. Our previous studies have indicated that the combination of chemotherapy with methionine restriction is often highly effective (18)(19)(20)(21)(22)(23)(24)(25)36).…”

Section: Discussionmentioning

confidence: 99%

“…The results indicate that o-rMETase can be an effective treatment to inhibit recurrent tumor growth in TNBC, as a cancer-specific metabolism-targeted therapy. Our previous experiments have shown o-rMETase holds much promise (19)(20)(21)(22)(23)(24)(25)(36)(37)(38), as it is an oral drug, despite being a large tetrameric protein, with no known side effects. We recently published a study on the long-term treatment with o-rMETase of a patient with bone-metastatic prostate cancer (38).…”

Section: Discussionmentioning

confidence: 99%

Oral Methioninase Inhibits Recurrence in a PDOX Mouse Model of Aggressive Triple-negative Breast Cancer

Lim

Hamada

Yamamoto

et al. 2020

In Vivo

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Background/Aim: The aim of the study was to use a triple-negative breast cancer (TNBC) patient-derived orthotopic xenograft (PDOX) model to examine the efficacy of oral recombinant methioninase (o-rMETase) against this recalcitrant disease. Materials and Methods: The TNBC tumor from a patient was implanted in the right 4 th inguinal mammary fat pad of nude mice. Two weeks later, the mice underwent tumorectomy with grossly-negative surgical margins. Two days after tumorectomy the mice were divided in two groups: one control and one treated with o-rMETase. Results: Tumors recurred in all mice. On day 11, the mean recurrent tumor volumes were 936.7 mm 3 in the control group and 450.9 mm 3 in the o-rMETase group (p<0.05). On day 15, the mean recurrent tumor volumes were 3392.5 mm 3 in the control group and 1603.5 mm 3 in the o-rMETase group. The mean recurrent tumor weights were 2.1 g in the control group and 1.1 g in the o-rMETase group on day 15. Conclusion: o-rMETase is an effective adjuvant treatment for aggressive TNBC. Breast cancer is the most common cause of cancer-related death among females worldwide (1). Between 15~20% of breast cancer patients are diagnosed with triple-negative breast cancer (TNBC) based on the absence of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER-2) (2). Unlike other types of breast cancer, TNBC has a poor prognosis with first-line chemotherapy such as anthracyclines and taxanes, and does not have additional treatment options, such as hormonal treatments or targeted therapy, following conventional first-line adjuvant chemotherapy. For this reason, novel therapeutics for TNBC are required, but this is still challenging. Methionine addiction is a fundamental and general hallmark of cancer (3). Methionine addiction, discovered by our laboratory, involves elevated methionine flux in cancer cells (4-6) due to elevated transmethylation-reactions (5, 7). Methionine overuse by cancer cells is known as the Hoffman effect, analogous to the Warburg effect of glucose overuse by cancer cells (8). Methionine restriction results in free-methionine and S-adenosylmethionine (SAM) depletion (6, 7, 9), and selective cell-cycle arrest in the S/G 2 phase in cancer cells (10, 11). Methionine addiction and DNA hypomethylation in human cancer, also discovered in our laboratory (12), are related (13, 14). Because methionine addiction is tightly linked to other features of cancer (15) and is a general phenomenon of cancer, it can be an important target for cancer treatment. Recently, Jeon et al. (16) observed that methionine restriction with a lowmethionine diet inhibited TNBC metastasis in mouse models. Recombinant methioninase (rMETase), a purified methioninecleaving enzyme, can target methionine addiction and can be used to treat any cancer by methionine restriction which selectively traps the cells in the S/G 2-phase of the cell cycle, where they are susceptible to most cytotoxic chemotherapy and can be successfully eradicated (17, 18). METase already ...

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“…Enhanced utilization of pathways adjacent to the methionine cycle to meet the demands of rapid biosynthesis may explain methionine addiction in cancer cells. Cancer therapeutics related to methionine metabolism have been used in clinical trials and focus on methionine depletion, thus affecting those cancers exhibiting methionine addiction [114,115]. L-methionine-α-amino-γ-mercaptoethane lyase or methioninase (METase) is an enzyme that converts methionine to α-ketobutyrate, methanethiol, and ammonia [114,115].…”

Section: Methionine Cyclementioning

confidence: 99%

“…Cancer therapeutics related to methionine metabolism have been used in clinical trials and focus on methionine depletion, thus affecting those cancers exhibiting methionine addiction [ 114 , 115 ]. L-methionine-α-amino-γ-mercaptoethane lyase or methioninase (METase) is an enzyme that converts methionine to α-ketobutyrate, methanethiol, and ammonia [ 114 , 115 ]. METase is being explored as a therapeutic and has shown efficacy in melanoma and Ewing sarcoma PDXes, and orthotopic models of osteosarcoma [ 116 , 117 , 118 ].…”

Section: Methionine Metabolismmentioning

confidence: 99%

Oncology Therapeutics Targeting the Metabolism of Amino Acids

Muhammad

Lee

Kim

2020

Cells

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Amino acid metabolism promotes cancer cell proliferation and survival by supporting building block synthesis, producing reducing agents to mitigate oxidative stress, and generating immunosuppressive metabolites for immune evasion. Malignant cells rewire amino acid metabolism to maximize their access to nutrients. Amino acid transporter expression is upregulated to acquire amino acids from the extracellular environment. Under nutrient depleted conditions, macropinocytosis can be activated where proteins from the extracellular environment are engulfed and degraded into the constituent amino acids. The demand for non-essential amino acids (NEAAs) can be met through de novo synthesis pathways. Cancer cells can alter various signaling pathways to boost amino acid usage for the generation of nucleotides, reactive oxygen species (ROS) scavenging molecules, and oncometabolites. The importance of amino acid metabolism in cancer proliferation makes it a potential target for therapeutic intervention, including via small molecules and antibodies. In this review, we will delineate the targets related to amino acid metabolism and promising therapeutic approaches.

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Efficacy of Recombinant Methioninase (rMETase) on Recalcitrant Cancer Patient-Derived Orthotopic Xenograft (PDOX) Mouse Models: A Review

Cited by 38 publications

References 74 publications

Methionine Dependence of Cancer

Methionine Dependence of Cancer

Oral Methioninase Inhibits Recurrence in a PDOX Mouse Model of Aggressive Triple-negative Breast Cancer

Oncology Therapeutics Targeting the Metabolism of Amino Acids

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