Table 3.

Anti-metabolic agents that can be combined with rapalogs to improve cytotoxic responses.

Drug	Target	Status of the drug	Current indications
NUCLEOTIDE METABOLISM
Gemcitabine	Ribonucleotide reductase	Approved	Solid cancers (pancreatic, colon, lung) and NH B-cell lymphomas
Fludarabine	DNA synthesis	Approved	CLL, NH B-cell lymphomas
Cytarabin	DNA synthesis	Approved	AML, ALL, CLL, CML, and NH lymphomas
Metothrexate	Dihydroxyfolate reductase (DHFR)	Approved	Solid cancers (lung, breast, bladder, placenta), ALL
AMINO ACID DEPLETION AND AMINO ACID METABOLISM
E-Coli-asparaginase Erwinase L-asparaginase, PEG-asparaginase	asparagine and glutamine	Approved	pediatric ALL Currently evaluated in adult leukemias, lymphomas and solid cancers
L-arginase	arginine	under clinical evaluation	Currently evaluated in pediatric ALL and AML, adult leukemia, lymphomas and solid cancers (kidney, liver)
CB-839	Glutaminase	under clinical evaluation	Current evaluation in ALL, AML, NH lymphomas and solid cancers (kidney, lung, skin, breast, colon)
ENERGETIC METABOLISM
Metformin	ETC complex I	approved	Type 2 diabete Currently evaluated in childhood and adult leukemias, lymphomas and solid cancers
AZD3965	MCT1	under clinical evaluation	Currently evaluated in solid cancer, DLBCL, and Burkitt lymphomas

NH B-cell lymphomas, Non-Hodgkin's B-cell lymphomas; CLL, Chronic Lymphocytic Leukemias; AML, Acute Myeloid Leukemia; ALL, Acute Lymphoblastic Leukemias; CML, Chronic Myeloid Leukemias.