Modulation of Oxidative Stress and Amino Acid Metabolism for the Treatment or Prevention of Diseases and Disorders

20250073321

18/954154

November 20, 2024

The present invention relates methods for treating cancer by comprising administering to the subject an agent for reducing at least one NEAA, inhibiting the PPP pathway, inhibiting the sorbitol pathway, inhibiting heme biosynthesis, or any combination thereof. The invention also includes methods of treating cancer comprising detecting a tumor as having increased ROS administering to the subject an agent for reducing at least one NEAA, inhibiting the PPP pathway, inhibiting the sorbitol pathway or inhibiting heme biosynthesis, or any combination thereof.

1. A method for treating or preventing tumor growth or metastasis in a subject in need thereof, the method comprising at least one of: a) increasing the level of reactive oxygen species (ROS) in the subject; b) administering a composition, or treatment regimen, for reducing the level of at least one amino acid selected from the group consisting of glutamate, glutamine, proline, serine, alanine, glycine, arginine, lysine, asparagine, methionine, threonine, and isoleucine; c) inhibiting the pentose phosphate pathway (PPP); d) inhibiting the sorbitol pathway; and e) inhibiting the heme biosynthesis pathway.

2. The method of claim 1, wherein the method of increasing the level of reactive oxygen species in the subject comprises at least one selected from the group consisting of: a) administering an inhibitor of Keap1; b) administering an inhibitor of glutathione (GSH); c) administering an activator of NRF2; d) administering an inhibitor of thioredoxin reductases; and e) administering an electrophile that reacts with Keap1 cysteines and leads to Nrf2 stabilization, to the subject.

3. The method of claim 2, wherein the inhibitor of Keap1 is selected from the group consisting of a chemical compound, a protein, a peptide, a peptidomemetic, an antibody, a ribozyme, a small molecule chemical compound, a nucleic acid, a vector, and an antisense nucleic acid molecule.

4. The method of claim 2, wherein the inhibitor of Keap1 is selected from the group consisting of KI-696 and an imidazole derivative of 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO-Im).

5. The method of claim 2, wherein the activator of NRF2 is selected from the group consisting of a chemical compound, a protein, a peptide, a peptidomemetic, an antibody, a ribozyme, a small molecule chemical compound, a nucleic acid, a vector, and an antisense nucleic acid molecule.

6. The method of claim 1, wherein the method comprises administering at least one composition comprising at least one selected from the group consisting of a chemical compound, a protein, a peptide, a peptidomemetic, an antibody, a ribozyme, a small molecule chemical compound, a nucleic acid, a vector, and an antisense nucleic acid molecule.

7. The method of claim 1, wherein the composition for reducing the level of at least one amino acid selected from the group consisting of glutamate, glutamine, proline, serine, alanine, glycine, arginine, lysine, asparagine, methionine, threonine, and isoleucine comprises at least one selected from the group consisting of an asparaginase, a serine degrading enzyme, an inhibitor of phosphoserine aminotransferase, an inhibitor of an amino acid transporter, wherein the amino acid is selected from the group consisting of glutamate, glutamine, proline, serine, alanine, glycine, arginine, lysine, asparagine, methionine, threonine, and isoleucine, an inhibitor of glutaminase (GLS), an inhibitor of glutamate dehydrogenase (GLUD), and an aminotransferase inhibitor.

8. The method of claim 1, wherein the asparaginase is selected from the group consisting of native asparaginase derived from Escherichia coli; a pegylated form of the native E. coli-asparaginase (polyethylene glycol-asparaginase); and an asparaginase enzyme isolated from Erwinia chrysanthemi.

9. The method of claim 1, wherein the serine degrading enzyme is L-serine ammonia lyase (SDH).

10. The method of claim 1, wherein the composition comprises at least one selected from the group consisting of GPNA, γ-FBP, benzylserine, BPTES, CB-839, compound 968, EGCG, R162, GCN2iA, 6-diazo-5-oxo-1-norleucine (DON) and AOA.

11. The method of claim 1, wherein the treatment regimen is dietary restriction.

12. The method of claim 1, wherein the agent for inhibiting the PPP pathway comprises an inhibitor of at least one selected from the group consisting of glucose-6-phosphate dehydrogenase (G6PD or G6PDH), 6-phosphogluconolactonase, 6-phosphogluconate dehydrogenase, fructose-bisphosphate aldolase B, ribose-5-phosphate isomerase, Ribulose 5-Phosphate 3-Epimerase, transaldolase, solute carrier family 16 member 1 (SLC16A1 or MCT1) and lactate dehydrogenase A (LDHA).

13. The method of claim 1, wherein the inhibitor of the PPP pathway is selected from the group consisting of dehydropiandrosterone (DHEA), N-(4-Hydroxynaphthalen-1-yl)-2,5-dimethylbenzenesulfonamide (CB-83), 6-Aminonicotinamide, SR13800, AZD 3965, R-GNE-140, NCI-006 and G6PDi-1.

14. The method of claim 1, wherein the agent for inhibiting the heme pathway comprises an inhibitor of at least one selected from the group consisting of 5-aminolevulinic acid synthase-1 (ALAS1), delta-aminolevulinic acid dehydratase (ALAD), hydroxymethylbilane synthase (HMBS), uroporphyrinogen III synthase (UROS), uroporphyrinogen decarboxylase (UROD), coproporphyrinogen oxidase (CPOX), protoporphyrinogen oxidase (PPOX), transmembrane protein 14C (TMEM14C), FLVCR heme transporter 1 (FLVCR1), solute carrier family 48 member 1 (SLC48A1) or ferrochelatase (FECH).

15. The method of claim 1, wherein the inhibitor of the heme pathway is selected from the group consisting of heme, 4,6-Dioxoheptanoic acid (Succinylacetone), 6-Methyl-PBG, PI-16, SH-11052 or glucose.

16. The method of claim 1, wherein the agent for inhibiting the sorbitol pathway comprises an inhibitor of at least one selected from the group consisting of sorbitol dehydrogenase (SORD), ketohexokinase, Triokinase and FMN Cyclase (TKFC), aldo-keto reductase family 1, member B1 (AKR1b1), aldo-keto reductase family 1, member B3 (AKR1b3), aldo-keto reductase family 1, member B7 (AKR1b7), aldo-keto reductase family 1, member B8 (AKR1b8), aldo-keto reductase family 1, member B10 (AKR1b10), sterol regulatory element binding protein-1c (SREBP-1c), Carbohydrate-responsive element-binding protein (ChREBP), fructose transporter solute carrier family 2 member 5 (SLC2A5 or GLUT5), solute carrier family 16 member 1 (SLC16A1 or MCT1) or lactate dehydrogenase A (LDHA).

17. The method of claim 1, wherein the inhibitor of the sorbitol pathway is selected from the group consisting of aldose reductase inhibitors, Epalrestat, KHK-IN-1 hydrochlorid, PF-06835919, 2,5-Anhydro-D-mannitol, SR13800, AZD 3965, R-GNE-140, or NCI-006.

18-20. (canceled)

61; 61; 61; 61; 61; 61; 61

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