ONCase (recombinant methionine α, γ-lyase)

AG-270 showed lack of cancer specificity in combination with rMETase when tested on both cancer and normal cells. The present results contrast with numerous chemotherapy agents, which in combination with rMETase are synergistic on cancer cells but not on normal cells. The present findings suggest that MAT2A inhibition affects crucial metabolic pathways in normal as well as cancer cell types and thus AG-270 may not be suitable as a cancer-specific therapeutic strategy.

The findings indicate that rMETase can overcome ultra-high doxorubicin resistance in fibrosarcoma cells, likely through targeting methionine addiction, a universal metabolic vulnerability of cancer. These results support the potential clinical application of methionine restriction therapy to treat doxorubicin-resistant STS.

Methionine restriction and olaparib showed synergistic efficacy on the BRCA1-mutant TNBC cell line HCC1937. The BRCA1-mutant cell line MDA-MB-436 was most sensitive to rMETase. The BRCA1/2 wild-type TNBC cell line MDA-MB-231 was sensitive to a methionine-free medium but resistant to olaparib. Therefore, methionine restriction has clinical potential for BRCA1/2 wild-type and BRCA1-mutant olaparib-resistant and -sensitive TNBC.

The present study suggests the synergy of methionine restriction and chemotherapy is due, at least in part, to DNA damage of cancer cells.

Methionine restriction consisting of o-rMETase and a low-methionine diet, in combination with first-line chemotherapy, was highly effective in a patient with inoperable stage IV pancreatic cancer.

Methionine restriction with rMETase up-regulates PD-L1 expression in human colorectal cancer cells and the combination of rMETase and ICIs may have the potential to improve immunotherapy in human colorectal cancer.

Methionine restriction consisting of o-rMETase and a low-methionine diet, in combination with T-DXd as second-line chemotherapy, was highly effective in a patient with HER2-positive stage IV breast cancer.

In the present study, we showed, for the first time, the synergistic combination efficacy of rMETase and ethionine on osteosarcoma cells in contrast to normal fibroblasts, which were relatively resistant. The combination of rMETase and ethionine down-regulated c-MYC expression in the cancer cells. The present results indicate the combination of rMETase and ethionine may reduce the malignancy of osteosarcoma cells and can be a potential future clinical strategy.

Addition of rMETase at 0.61 U/ml lowered the IC of regorafenib from 2.26 μM to 1.46 μM. rMETase and regorafenib are synergistic, giving rise to the possibility of lowering the effective dose of regorafenib in patients, thereby reducing its severe toxicity, allowing more cancer patients to be treated with regorafenib.

Methionine restriction comprising o-rMETase and a low-methionine diet combined with first-line chemotherapy was effective in a patient with NRAS-mutant rectal cancer in which metastasis had re-occurred after first-line chemotherapy alone.

The present study suggests that rMETase has future potential therapy for CCLM in the clinic.

Combination therapy of doxorubicin and cyclophosphamide followed by docetaxel combined with methionine restriction led to a remarkable complete response that is expected in fewer than 10% of patients with ILC of the breast treated with neo-adjuvant chemotherapy alone. The present results suggest that methionine restriction in combination with doxorubicin and cyclophosphamide followed by docetaxel may be effective, after METPET has demonstrated the presence of methionine-addicted axillary-lymph-node metastases in ILC of the breast.