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

Abstract

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 ...

Response of Triple-negative Breast Cancer Liver Metastasis to Oral Recombinant Methioninase in a Patient-derived Orthotopic Xenograft (PDOX) Model

“…o-rMETase has already shown promise in the clinic (28) and will soon be tested on TNBC patients, especially with liver metastasis. o-rMETase has previously shown efficacy to inhibit post-surgical recurrence of TNBC in a PDOX nude-mouse model (30). This new PDOX model of TNBC liver metastasis has potential to identify curative therapeutics for this recalcitrant disease, especially using o-rMETase instead of injectable rMETase which can cause immunological reactions (31), unlike o-rMETase (28), and will therefore, be suitable clinically in the near future for TNBC.…”

Oral-recombinant Methioninase Converts an Osteosarcoma from Methotrexate-resistant to -sensitive in a Patient-derived Orthotopic-xenograft (PDOX) Mouse Model

“…r-METase effectively degrades external methionine (63). The efficacy of orally-administrated r-METase (o-rMETase) was shown previously shown in many types of cancer in PDOX models (18,21,22,(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(51)(52)(53)(54)(55)(56)(57)(58). We have also reported the efficacy of rMETase on PDOX models of osteosarcoma including o-rMETase (8,10,18,21,22).…”

“…o-rMETase has also been shown to prevent obesity, diabetes and fatty liver in mouse models (47)(48)(49). o-rMETase has also shown apparent clinical efficacy in advanced prostate cancer (50), reflecting its efficacy in PDOX models of advanced cancers (51)(52)(53)(54)(55)(56)(57)(58).…”

Methionine Restriction: Ready for Prime Time in the Cancer Clinic?

“…For example, o-rMETase could overcome gemcitabine resistance in a PDOX model of pancreatic cancer (25). o-rMETase overcame chemotherapy-resistance in sarcoma (26)(27)(28) and triple-negative breast cancer (29,30). Early clinical studies have shown that o-rMETase decreases or stabilizes prostate specific antigen (PSA) levels in patients with advanced-prostate cancer with no adverse effects (31)(32)(33).…”