Targeting arginine-dependent cancers with arginine-degrading enzymes: opportunities and challenges

Area of Science:

• Oncology
• Biochemistry
• Metabolic Therapy

Background:

• Arginine deprivation is an emerging antimetabolite cancer treatment strategy.
• It targets cancers dependent on exogenous arginine due to urea cycle enzyme dysregulation, particularly argininosuccinate synthetase 1 (ASS1).
• Epigenetic silencing of ASS1 is a common mechanism causing tumor arginine auxotrophy.

Purpose of the Study:

• To review the novel strategy of arginine deprivation for cancer treatment.
• To discuss the role of urea cycle enzymes, ASS1 and argininosuccinate lyase, in cancer arginine dependence.
• To highlight ongoing clinical trials and future challenges for arginine-targeted therapies.

Main Methods:

• Review of scientific literature on arginine metabolism in cancer.
• Analysis of mechanisms of tumor arginine dependence, including ASS1 inactivation and argininosuccinate lyase dysregulation.
• Examination of clinical trial data for arginine-depleting agents like ADI-PEG20.

Main Results:

• ASS1 inactivation is implicated in various cancers (melanoma, HCC, etc.), leading to arginine dependence.
• Argininosuccinate lyase dysregulation is observed in glioblastoma, HCC, and renal cancers.
• Pegylated arginine deiminase (ADI-PEG20) is in late-stage clinical trials.

Conclusions:

• Arginine deprivation is a promising therapeutic strategy for specific cancer types.
• Identifying sensitive tumors and predicting response using biomarkers are critical challenges.
• Further research into resistance pathways is necessary for optimizing arginine-targeted therapies.