Pegargiminase is an enzyme-based therapy for certain cancers. This medication targets the metabolic vulnerabilities of cancer cells, aiming to disrupt their growth and survival. It focuses on specific characteristics of tumor cells to improve therapeutic outcomes. Ongoing research and clinical trials continue to explore its full potential in various cancer types.
What is Pegargiminase?
Pegargiminase, also known as ADI-PEG 20 or pegzilarginase, is a modified enzyme designed to deplete the amino acid arginine from the bloodstream. This synthetic enzyme is derived from bacterial arginine deiminase (ADI) and is combined with polyethylene glycol (PEG). The PEGylation process helps the enzyme remain in the body for a longer duration and reduces the likelihood of an immune reaction against the drug.
The primary purpose of pegargiminase is to lower the circulating levels of arginine. Arginine is an amino acid that many cancer cells require to grow and proliferate. By removing this essential nutrient, pegargiminase aims to starve these specific cancer cells, thereby inhibiting their ability to multiply and spread.
How Pegargiminase Works
The mechanism of action for pegargiminase centers on a metabolic vulnerability in certain cancer cells. Many healthy cells produce their own arginine using the enzyme argininosuccinate synthetase 1 (ASS1). However, many cancer cells lack or have very low ASS1 expression, making them unable to synthesize arginine internally.
This deficiency makes these cancer cells “arginine auxotrophic,” meaning they depend on external arginine from the bloodstream to survive and grow. Pegargiminase exploits this dependency by breaking down arginine into citrulline and ammonia in the blood. This depletes the arginine supply for auxotrophic cancer cells, leading to metabolic stress and cell death.
By removing this supply, pegargiminase selectively starves tumor cells while sparing healthy cells, which can still produce or acquire their own arginine. This targeted approach aims to reduce tumor growth and enhance the effectiveness of other cancer treatments.
Medical Applications of Pegargiminase
Pegargiminase is being investigated for its application in several cancer types that exhibit arginine auxotrophy. A notable focus is mesothelioma, particularly non-epithelioid subtypes like biphasic and sarcomatoid mesothelioma, where ASS1 deficiency is common. In clinical trials, such as the ATOMIC-Meso study, pegargiminase combined with chemotherapy showed improved overall survival and delayed cancer progression in patients with nonepithelioid pleural mesothelioma.
Beyond mesothelioma, pegargiminase has shown promise in other arginine-dependent tumors. Early studies have explored its activity in malignant melanoma and hepatocellular carcinoma, where similar ASS1 deficiencies can occur. Research also includes investigations into acute myeloid leukemia (AML), soft tissue sarcoma, and non-small cell lung cancer, among others, where ASS1 expression is frequently downregulated.
Patient selection for pegargiminase therapy is based on identifying tumors that lack ASS1 expression. This biomarker-driven approach ensures treatment is directed towards cancers most likely to respond to arginine depletion. The drug is often studied in combination with standard chemotherapy regimens to increase cancer cell sensitivity to conventional treatments.
Administering Pegargiminase and Managing Side Effects
Pegargiminase is administered through intramuscular injection, often weekly. In clinical trial settings, it has been given in combination with intravenous chemotherapy, such as pemetrexed and platinum-based drugs, every three weeks for several cycles. The treatment regimen can continue for an extended period, up to two years, depending on the patient’s response and disease stage.
Pegargiminase can cause side effects, which are generally mild. Common adverse events observed in clinical trials include nausea, fatigue, constipation, and vomiting. Some patients may also experience tenderness at the injection site.
More severe, though less frequent, side effects can include hypersensitivity reactions, skin reactions, or systemic toxicity. Medical professionals closely monitor patients during treatment to manage any side effects and ensure their comfort and safety. This includes monitoring for potential combined toxicities when pegargiminase is used alongside chemotherapy.