Significance The survival of many malignancies critically depends on l-methionine (l-Met) needed for S-adenosyl-methionine formation, protein synthesis, cysteine production, and polyamine synthesis. Partial dietary l-Met restriction or the administration of bacterial l-Met–degrading enzymes displays potent antitumor effects in multiple murine cancer models. Bacterial l-Met–degrading enzymes are problematic due to immunogenicity, and dietary restriction is not practical or desirable in some therpaeutic settings. Here we describe the development of an engineered human enzyme (hMGL-4.0) that reduces systemic l-Met levels and significantly inhibits the growth of multiple prostate cancer allografts/xenografts without weight loss or toxicity, even when administered for over a month. Our data suggests hMGL-4.0 represents a drug candidate targeting the l-Met metabolic vulnerability in prostate and other cancers.
Extensive studies in prostate cancer and other malignancies have revealed that l-methionine (l-Met) and its metabolites play a critical role in tumorigenesis. Preclinical and clinical studies have demonstrated that systemic restriction of serum l-Met, either via partial dietary restriction or with bacterial l-Met–degrading enzymes exerts potent antitumor effects. However, administration of bacterial l-Met–degrading enzymes has not proven practical for human therapy because of problems with immunogenicity. As the human genome does not encode l-Met–degrading enzymes, we engineered the human cystathionine-γ-lyase (hMGL-4.0) to catalyze the selective degradation of l-Met. At therapeutically relevant dosing, hMGL-4.0 reduces serum l-Met levels to >75% for >72 h and significantly inhibits the growth of multiple prostate cancer allografts/xenografts without weight loss or toxicity. We demonstrate that in vitro, hMGL-4.0 causes tumor cell death, associated with increased reactive oxygen species, S-adenosyl-methionine depletion, global hypomethylation, induction of autophagy, and robust poly(ADP-ribose) polymerase (PARP) cleavage indicative of DNA damage and apoptosis.