TY - JOUR T1 - Combination Methionine-methylation-axis Blockade: A Novel Approach to Target the Methionine Addiction of Cancer JF - Cancer Genomics - Proteomics JO - Cancer Genomics Proteomics SP - 113 LP - 120 DO - 10.21873/cgp.20246 VL - 18 IS - 2 AU - TAKASHI HIGUCHI AU - QINGHONG HAN AU - NORIHIKO SUGISAWA AU - JUN YAMAMOTO AU - NORIO YAMAMOTO AU - KATSUHIRO HAYASHI AU - HIROAKI KIMURA AU - SHINJI MIWA AU - KENTARO IGARASHI AU - MICHAEL BOUVET AU - SHREE RAM SINGH AU - HIROYUKI TSUCHIYA AU - ROBERT M. HOFFMAN Y1 - 2021/03/01 UR - http://cgp.iiarjournals.org/content/18/2/113.abstract N2 - 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. ER -