Efficacy of Oral Recombinant Methioninase and Eribulin on a PDOX Model of Triple-negative Breast Cancer (TNBC) Liver Metastasis

Abstract

Background/Aim: The aim of the present study was to identify effective drugs for a highly-aggressive livermetastasis of triple-negative breast cancer (TNBC) in a patientderived orthotopic xenograft (PDOX) mouse model. Drugs tested were oral recombinant methioninase (o-rMETase), lowdose eribulin and their combination. Materials and Methods: Patient-derived TNBC was implanted in the liver of nude mice by surgical hepatic implantation. Two weeks after transplantation, 32 mice were randomized (n=8 per group) into a phosphate-buffered saline vehicle-control group; o-rMETasetreatment group (100 units, o-rMETase, oral, daily for 2 weeks); eribulin-treatment group (0.05 mg/kg intraperitoneally once per week for 2 weeks); or combination-treatment group (100 units r-METase, oral, daily for 2 weeks + 0.05 mg/kg eribulin intraperitoneally once per week for 2 weeks). Results: After 2 weeks, the three treatment groups exhibited significantlyinhibited TNBC growth in the liver compared to the vehiclecontrol group (p≤0.05). Conclusion: o-rMETase and low-dose eribulin monotherapy and their combination were efficacious against the highly-aggressive TNBC PDOX growing in the liver. The TNBC PDOX model can be used to identify highly-effective drugs for therapy of TNBC with liver metastasis.Triple-negative breast cancer (TNBC) is negative for estrogen receptor, progesterone receptor and human epidermal-growth-factor receptor 2 (1). TNBC is highly recalcitrant to chemotherapy such as anthracyclines and taxanes and has very poor prognosis, as most patients die of metastatic disease (2, 3).Eribulin is an anti-microtubule agent that prevents microtubule polymerization with anti-mitotic activity. Recently, eribulin was shown to be active clinically against metastatic breast cancer, increasing overall survival in the EMBRACE trial (4).The patient-derived orthotopic xenograft (PDOX) mouse model, which mimics clinical cancer, was developed by our laboratory in 1991 (5). We established the first PDOX model of breast cancer, which showed metastases to the lung in 1993 (6). We previously developed PDOX models of TNBC (7-10) and showed the primary tumor to be sensitive to eribulin and oral recombinant methioninase (o-rMETase). We also developed a liver-metastasis PDOX model of TNBC (11). In the present study, we show that the liver-metastasis PDOX model is sensitive to low-dose eribulin and o-rMETase and their combination. Materials and MethodsMice. Female nu/nu nude female mice (AntiCancer Inc., San Diego, CA, USA), 4-6 weeks old, were used in this study. The breeding and maintenance of the nude mice are described in our previous reports (7,8). All mouse studies were carried out under the National Institutes of Health Guide for the Care and Use of Animals (Assurance Number A3873-1).Patient-derived TNBC and establishment of PDOX with liver metastasis. The TNBC tissue used was from a 74-year-old female patient diagnosed with invasive ductal-carcinoma in the right breast. Breast-conserving surgery was performed at the Department of Surgery, Samsung ...

Validation of a Patient-Derived Xenograft Model for Cervical Cancer Based on Genomic and Phenotypic Characterization

“…PDX models reproduce the clinicopathological characteristics of the original tumor and are used as experimental models for drug evaluation, biomarker identification, and precision medicine strategies [ 6 ]. Several PDX models have been established successfully, including colon [ 9 ], stomach [ 10 ], breast [ 11 ], pancreas [ 12 ], lung [ 13 ], liver [ 14 ], kidney [ 15 ], bladder [ 16 ], uterus [ 17 ], and ovary [ 18 ]. However, a limited number of studies have reported PDX models of cervical cancer.…”

Oral Installation of Recombinant Methioninase-producingEscherichia coliinto the Microbiome Inhibits Colon-cancer Growth in a Syngeneic Mouse Model

“…Although we have previously reported the efficacy of oral rMETase in many types of cancer in vivo (40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(61)(62), this is the first report that shows oral administration of E. coli JM109-rMETase inhibits tumor growth. When E. coli is administered orally, its toxicity to mice should be considered.…”

“…rMETase was initially administered by intravenous or intraperitoneal injection. However, recently we showed that rMETase was highly effective when administered orally (40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54). However, oral administration of methioninase requires multiple doses each day.…”

Elimination of Axillary-Lymph-Node Metastases in a Patient With Invasive Lobular Breast Cancer Treated by First-line Neo-adjuvant Chemotherapy Combined With Methionine Restriction

“…We originally discovered that methionine restriction is highly synergistic with chemotherapy in 1986 (28). Since that original publication, many studies have shown synergy of methionine restriction with chemotherapy (32,33), including methionine restriction with rMETase (15,(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44). The combination of methionine restriction and chemotherapy is termed the Hoffman protocol (45).…”

“…We have produced recombinant methioninase (rMETase) (12), an enzyme that catabolizes methionine, and have demonstrated the effectiveness of rMETase in breast cancer using patientderived orthotopic xenograft (PDOX) models (13)(14)(15)(16).…”