Glutamine is the most abundant non-essential amino acid in the bloodstream. It is a foundational element for cellular growth and proliferation, acting as a source of both nitrogen and carbon for various biosynthetic pathways. Cancer cells exhibit a dramatically altered metabolism, becoming highly dependent on external nutrients to sustain their rapid growth. Targeting these distinctive metabolic demands offers a therapeutic strategy aimed at disrupting the cell’s energy and building-block supply lines by focusing on enzymes that cancerous cells rely upon more heavily than normal cells.
The Central Role of Glutamine Metabolism
Rapidly dividing cells, such as cancer cells, demonstrate a high rate of glutamine uptake and utilization. Glutamine provides carbon atoms to replenish the tricarboxylic acid (TCA) cycle, which is necessary for sustained energy production and biosynthesis. It also supplies nitrogen for the synthesis of new proteins and the purine and pyrimidine bases required to build DNA and RNA.
The initial step in breaking down glutamine, called glutaminolysis, is catalyzed by the enzyme glutaminase (GLS). GLS hydrolyzes the amide group of glutamine, converting it into glutamate and releasing a molecule of ammonia. The resulting glutamate is then further metabolized to alpha-ketoglutarate, which feeds directly into the TCA cycle. Glutamine also plays a role in maintaining redox homeostasis by providing a precursor for glutathione, a primary cellular antioxidant.
How Glutaminase Inhibitors Function
Glutaminase inhibitors (GIs) interrupt the glutaminolysis pathway by blocking the activity of the glutaminase enzyme. By preventing the conversion of glutamine to glutamate, these drugs starve the cell of metabolic intermediates. The resulting lack of glutamate starves the TCA cycle and restricts the cell’s ability to synthesize new nucleotides and lipids, thereby halting proliferation.
The glutaminase enzyme has two primary isoforms in humans, GLS1 and GLS2, which are encoded by distinct genes and have different tissue distributions. GLS1 is the isoform frequently overexpressed in many tumor types and is the main target of current inhibitors. GLS2 may act as a tumor suppressor in some contexts, complicating pan-GLS inhibition strategies.
GIs can function through different mechanisms, such as being competitive or allosteric. Competitive inhibitors bind to the enzyme’s active site. Allosteric inhibitors bind to a different site on the enzyme to change its shape and render it inactive.
Glutaminase Inhibitors in Cancer Treatment
The therapeutic application of glutaminase inhibitors is primarily focused on oncology, leveraging the metabolic dependency of cancer cells. Drugs like Telaglenastat, a highly selective, orally available GLS1 inhibitor, have been extensively tested in clinical trials for various solid and hematologic malignancies. Telaglenastat aims to inhibit the elevated GLS1 activity commonly found in cancers such as clear cell renal cell carcinoma (ccRCC) and triple-negative breast cancer (TNBC).
Glutaminase inhibitors are frequently studied in combination with other anti-cancer treatments due to the metabolic flexibility of tumors. Combining GIs with other agents disrupts multiple metabolic pathways and potentially offers synergistic effects. This combination strategy can overcome resistance mechanisms that cancer cells may activate when only glutaminolysis is blocked.
The inhibition of glutamine metabolism can also enhance the effect of immunotherapy by influencing the tumor microenvironment. Glutamine deprivation can increase the expression of programmed death-ligand 1 (PD-L1) on tumor cells, and combination with immune checkpoint inhibitors is an active area of research. The lack of glutamine also reduces the level of glutathione, increasing the cancer cell’s oxidative stress and making them more susceptible to cell death from other treatments. The concept of synthetic lethality, where a targeted therapy exploits a specific genetic defect in the cancer cell, is also being explored by combining GLS inhibitors with drugs that target other vulnerabilities.
Observed Side Effects and Safety Profile
The inhibition of a fundamental metabolic pathway like glutaminolysis necessitates careful monitoring for adverse effects, as glutamine is used by many normal, non-cancerous cells. Clinical trials involving glutaminase inhibitors like Telaglenastat have generally indicated a tolerable safety profile. The most frequently reported adverse events are often mild to moderate and generally manageable.
Common side effects observed in clinical studies include gastrointestinal issues such as nausea and vomiting, which can be expected when altering nutrient metabolism. Fatigue is another frequently reported adverse event, along with potential liver enzyme abnormalities, specifically transaminitis, which involves elevated levels of liver enzymes.
Older, less selective glutamine antimetabolites, such as DON, historically caused more severe dose-limiting toxicities, including neurotoxicity and bone marrow suppression, due to their broad inhibition of other glutamine-utilizing enzymes. Newer, more selective GLS1 inhibitors, like Telaglenastat, are designed to mitigate these severe systemic side effects by focusing their action on the isoform most prevalent in tumors.
While the goal is to target cancer cells, some normal cells, particularly in the gastrointestinal tract and the immune system, still rely on glutamine, which accounts for the observed gastrointestinal and fatigue-related adverse effects. The overall safety profile suggests that these inhibitors are viable candidates for combination therapy without significantly increasing the toxicity burden of existing treatments.