Targeting amino acid metabolism in cancer growth and anti-tumor immune response

Table 1 Amino acid metabolic enzymes targeted in cancer therapy

Amino acidmetabolism	Targeted enzyme	Drug design	Drug toxicity, adverse events	Cancer type	Response rate	Clinical studies	Ref.
Arginine	ASS1, Arginine deaminase	ADI-PEG20	1Grade 3-4: Fatigue, hyperuricemia, anemia	HCC (nonresectable and metastatic)	31%-47%	Phase I/II	[30,94,95]
	.	ADI-PEG20	1Grade 3-4: Pain in extremity, arthralgia, pruritus, lymphedema, seizure	Melanoma (stage III and IV)	25%	Phase I/II	[96,97]
	Arginase 1	rhArgIpeg5000	1Grade 3-4: Elevated ALT, AST, bilirubin and GGT	HCC (advanced)	26.70%	Phase I	[31]
		Co-hArgI	Nude BALBc mouse model: Weight loss, hunch posture, lethargy, bone marrow injuries (> 15 mg/kg)	HCC (HepG2), pancreatic cancer (Panc-1); tumor site (right flank)	Smaller tumors	Preclinical studies	[98]
Tryptophan	IDO	Indoximod and docetaxel	Grade 1: Anemia, fatigue, hyperglycemia Grade 3-4: Headache, hypotension, infection	Various metastatic solid tumors	41% PD	Phase I	[99]
		1-D-MT	Grade 1: Fatigue; Grade 2: Hypophysitis	Various metastatic solid tumors	4P (SD), 3P (PD)	Phase I	[100]
		Indoximod and anti-CTLA4	C57BL/6 mouse model: No weight loss or acute/delayed toxicity observed	B16 F10 melanoma cell line, tumor site -flank	Delayed tumor growth	Preclinical studies	[101]
Tryptophan	TDO	Indole LM10	DBA/2 mouse model: No liver toxicity observed for 3 mo	P815B tumor cell line, tumor site –peritoneal cavity	Delayed tumor progression	Preclinical studies	[50]
Serine	PHGDH	NA	NA	Melanoma and breast cancer cell lines (SkBr3, MCF7)	NA	Preclinical studies	[15]
		NA	NA	Murine mammary fat pad tumors with MDA-MB-468 cells expressing PHGDH-shRNA	Reduced tumor growth	Preclinical studies	[63]
Glycine	SHMT1	NA	λ-Myc Shmt1-/- transgenic mice: no toxicity observed	Accelerated lymphomagenesis	NA	Preclinical studies	[102]
Glutamine	Glutamine –dependent enzymatic steps	L-DON2, azaserine2	None reported	Various animal and human xenografted tumors	Tumor growth inhibition	Preclinical studies	[80]
		Acivicin2	Grade1-3: neurological toxicity Grade 2: vomiting, infections	High grade astrocytoma	Median 128 day survival	PhaseII	[103]
Leucine, Isoleucine, Valine	BCATc	NA	CD-1 nude mouse model bearing tumors with BCATc knockdown: lethargy and uncoordinated motor activity	U-87MG glioblastoma cells with BCATc-shRNA; tumor site-intracerebral transplantation	Smaller tumors	Preclinical studies	[16]
		NA	NA	Nasopharyngeal carcinoma (5-8F, 6-10B), colorectal cancer	Induced cell proliferation	Preclinical studies	[92,93]

¹The highest grade is shown (Grade 3-4) and is summarized for either one or more studies;

²Discontinued. ADI-PEG20: Pegylated arginine deiminase; rhArgIpeg5000: Pegylated recombinant human arginase I; HCC: Hepatocellular carcinoma; Co-hArgI: Co²⁺ substitution of the Mn²⁺ metal cofactor in human arginase I; Indoximod (NLG8189, 1-D-MT1): 1-methyl-D-tryptophan; Indole LM10, tetrazolyl-vinyl substituted (fluoro)indole; L-DON: 6-diazo-5-oxo-L-norleucine; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gamma glutamyltransferase; PD: Progressed disease; SD: Stable disease; P: Patient; NA: Not available.