Aeglea BioTherapeutics’ investigational enzyme, AEB3103, seems a promising treatment approach for a number of tumors, according to preclinical study results. The therapy suppressed tumor growth in prostate and breast cancer mouse models, and improved survival in a model of chronic lymphocytic leukemia (CLL).
These findings, published in the journal Nature Medicine, were detailed in the study, “Systemic Depletion Of Serum L-Cyst(E)Ine With An Engineered Human Enzyme Induces Production Of Reactive Oxygen Species And Suppresses Tumor Growth In Mice.”
High activity within cells leads to the production of unstable molecules called reactive oxygen species (ROS) within the mitochondria (the cell’s powerhouse). Usually, cells use antioxidants, such as the protein glutathione, to ‘clean’ themselves of ROS. But when ROS are produced at too fast a pace and accumulate, antioxidant defenses are not enough to protect cells from their damaging effects.
Cancer cells experience greater oxidative stress than healthy cells due to the genetic alterations they harbor and their abnormal growth. As such, maintaining antioxidant defenses against ROS is crucial to cancer’s survival and growth.
In the studies, AEB3103 given to mice with prostate or breast cancer, or used in a model of human CLL, deprived cancer cells of an important activator of the antioxidant glutathione, called L-cysteine. Its lack promoted ROS accumulation, increasing oxidative damage to, and cell death in, the cancer cells.
AEB3103, an engineered human enzyme, works to degrade L-cysteine in the blood into non-toxic metabolites.
“These preclinical results suggest that the use of AEB3103 to deplete the amino acid L-cysteine has the potential to be a well-tolerated approach for treating tumors with high levels of ROS,” David Lowe, PhD, president and CEO of Aeglea, said in a news release. “The idea of targeting cancer with an enzyme that degrades L-cysteine was first proposed in 1961. Since then, the evidence that this is an important and unexploited vulnerability of cancer has been widely described but not effectively applied for therapeutic benefit.”
Tumor cells defend themselves against ROS by absorbing L-cysteine and its oxidized form, L-cystine, from the blood, the company reported in the release. Their reliance on extracellular L-cysteine for growth is well-established in prostate cancer, triple negative breast cancer, and other solid tumors, as well as in hematological malignancies like myeloma, acute myelogenous leukemia and CLL.
“As many other chemotherapeutic agents are also known to oxidatively stress cancer cells, we are looking forward to exploring AEB3103 in combination with ROS-inducing drugs as a potential cancer treatment,” said George Georgiou, PhD, a study author and Aeglea co-founder.