RT Journal Article SR Electronic T1 Combination Methionine-methylation-axis Blockade: A Novel Approach to Target the Methionine Addiction of Cancer JF Cancer Genomics - Proteomics JO Cancer Genomics Proteomics FD International Institute of Anticancer Research SP 113 OP 120 DO 10.21873/cgp.20246 VO 18 IS 2 A1 TAKASHI HIGUCHI A1 QINGHONG HAN A1 NORIHIKO SUGISAWA A1 JUN YAMAMOTO A1 NORIO YAMAMOTO A1 KATSUHIRO HAYASHI A1 HIROAKI KIMURA A1 SHINJI MIWA A1 KENTARO IGARASHI A1 MICHAEL BOUVET A1 SHREE RAM SINGH A1 HIROYUKI TSUCHIYA A1 ROBERT M. HOFFMAN YR 2021 UL http://cgp.iiarjournals.org/content/18/2/113.abstract AB Background/Aim: Cancers are selectively sensitive to methionine (MET) restriction (MR) due to their addiction to MET which is overused for elevated methylation reactions. MET addiction of cancer was discovered by us 45 years ago. MR of cancer results in depletion of S-adenosylmethionine (SAM) for transmethylation reactions, resulting in selective cancer-growth arrest in the late S/G2-phase of the cell cycle. The aim of the present study was to determine if blockade of the MET-methylation axis is a highly-effective strategy for cancer chemotherapy. Materials and Methods: In the present study, we demonstrated the efficacy of MET-methylation-axis blockade using MR by oral-recombinant methioninase (o-rMETase) combined with decitabine (DAC), an inhibitor of DNA methylation, and an inhibitor of SAM synthesis, cycloleucine (CL). We determined a proof-of-concept of the efficacy of the MET-methylation-axis blockade on a recalcitrant undifferentiated/unclassified soft-tissue sarcoma (USTS) patient-derived orthotopic xenograft (PDOX) mouse model. Results: The o-rMETase-CL-DAC combination regressed the USTS PDOX with extensive cancer necrosis. Conclusion: The new concept of combination MET-methylation-axis blockade is effective and can now be tested on many types of recalcitrant cancer.