Modulation of oxidative stress and amino acid metabolism for the treatment or prevention of diseases and disorders
Inventors
Assignees
Publication Number
US-12186377-B2
Publication Date
2025-01-07
Expiration Date
2040-09-23
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Abstract
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.
Core Innovation
The invention provides methods for treating or preventing tumor growth or metastasis by targeting specific metabolic dependencies in cancer cells. It is based on the discovery that genetic, pharmacologic, or ROS-dependent activation of the NRF2 antioxidant response pathway creates a dependency on multiple nonessential amino acids (NEAAs). This is mediated by NRF2-driven excretion of glutamate via the system xc− antiporter, limiting intracellular glutamate availability for NEAA synthesis and thus making cancer cells reliant on uptake of exogenous NEAAs.
The problem addressed by the invention is the limited understanding and effectiveness of current metabolic therapies targeting cancer, especially in tumors with genetic alterations in the KEAP1/NRF2 pathway. Such tumors undergo metabolic reprogramming, becoming dependent on exogenous glutamine and other NEAAs to support their antioxidant response and proliferation. Maintaining oxidative homeostasis through chronic NRF2 activation results in unique metabolic requirements that can be exploited therapeutically.
Consequently, the invention describes methods for suppressing tumor growth by administering agents that reduce at least one NEAA, inhibit the pentose phosphate pathway (PPP), inhibit the sorbitol pathway, inhibit heme biosynthesis, or by increasing reactive oxygen species (ROS) levels in tumor cells, either individually or in combination. The invention also includes methods involving detection of specific metabolic or genetic markers (such as decreased Keap1 activity or increased NRF2 activity) in tumors and tailored administration of these agents or dietary regimens to target the cancer's metabolic vulnerabilities.
Claims Coverage
There are four main inventive features covered by the independent claim, each targeting a distinct metabolic pathway or dependency for treating or preventing tumor growth or metastasis.
Detection of Keap1 alterations as a basis for therapy
The invention provides for detecting decreased Keap1 activity or the presence of an inactivating mutation of Keap1 in a tumor prior to treatment. This detection step identifies tumors with altered regulation of the NRF2 pathway, facilitating targeted intervention based on metabolic vulnerabilities.
Reduction of nonessential amino acid levels using specific agents
A treatment involves administering a composition or regimen to reduce the level of at least one amino acid selected from glutamate, glutamine, proline, serine, alanine, glycine, arginine, lysine, asparagine, methionine, threonine, or isoleucine. The reduction is achieved via agents such as asparaginase, serine degrading enzymes, inhibitors of phosphoserine aminotransferase, amino acid transporters, glutaminase (GLS), glutamate dehydrogenase (GLUD), aminotransferase inhibitors, or competitive glutamine inhibitors.
Inhibition of the pentose phosphate pathway (PPP)
The method includes administering an agent that inhibits enzymes of the PPP, specifically targeting 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, SLC16A1 (MCT1), or lactate dehydrogenase A (LDHA). This aims to disrupt NADPH production critical for cancer cell survival under oxidative stress.
Inhibition of the sorbitol and heme biosynthesis pathways
The method enables treating or preventing tumor growth by administering agents that inhibit: (a) the sorbitol pathway (targeting enzymes like SORD, ketohexokinase, TKFC, various aldo-keto reductases, SREBP-1c, ChREBP, GLUT5, SLC16A1, or LDHA); and/or (b) the heme biosynthesis pathway (targeting enzymes such as ALAS1, ALAD, HMBS, UROS, UROD, CPOX, PPOX, TMEM14C, FLVCR1, SLC48A1, or FECH).
The inventive features provide a multi-faceted approach to cancer therapy by identifying tumors with metabolic vulnerabilities and administering specific agents to reduce amino acid availability or inhibit critical metabolic pathways including the PPP, sorbitol, and heme biosynthesis, to suppress tumor growth or metastasis.
Stated Advantages
Provides a novel metabolic strategy to target cancers with activation of the Nrf2 antioxidant response pathway by restricting exogenous sources of nonessential amino acids.
Enables suppression of tumor growth by dietary or enzymatic depletion of specific amino acids, especially in tumors with Keap1/NRF2 alterations.
Allows therapeutic exploitation of the metabolic dependency on exogenous nonessential amino acids induced by NRF2 activation in cancer cells.
Facilitates synthetic lethality by combining inhibition of specific metabolic pathways (such as PPP, sorbitol, or heme biosynthesis) with loss or inhibition of Keap1/NRF2 signaling.
Documented Applications
Treatment or prevention of tumor growth or metastasis in subjects with tumors exhibiting decreased Keap1 activity or inactivating Keap1 mutations.
Therapeutic targeting of cancers characterized by increased ROS, increased NRF2 activity, or mutations leading to NRF2 activation, including but not limited to lung and pancreatic cancers.
Use of specific metabolic inhibitors or dietary interventions to modulate NEAA levels, the pentose phosphate pathway, the sorbitol pathway, and heme biosynthesis in cancer treatment.
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