Tumor metabolism as a target for therapy
Arginine and lysine are critical amino acids for the growth of human cancers. In addition to protein synthesis, arginine is involved in diverse aspects of tumor metabolism including the synthesis of nitric oxide, polyamines, nucleotides, proline, and glutamate. Downregulation of the enzyme argininosuccinate synthetase (ASS1) in tumors, a recognized rate–limiting step in arginine synthesis, results in an intrinsic dependence on extracellular arginine due to an inability to synthetize arginine for growth. This dependence on extracellular arginine is known as arginine auxotrophy. Several tumors are arginine auxotrophic, including hepatocellular carcinoma, malignant melanoma, malignant pleural mesothelioma, prostate and renal cancer.
Aplysia punctata Ink Toxin (APIT) is a L-amino acid oxidase that oxidizes and thereby depletes the amino acids L-lysine and L-arginine in addition to producing reactive oxygen species (ROS) such as hydrogen peroxide and oxygen radicals (ROS) in the process. When used on cancers, ONCAREX (PEGylated APIT) specifically targets tumor cells in different ways: it starves the rapidly dividing and metabolizing tumor cells for the two amino acids L-lysine and L-arginine. In addition, it exposes tumor cells to the tumoricidal action of ROS. Importantly, APIT induces a non-apoptotic mode of cell death and is thus a potent killer of apoptosis resistant and multidrug resistant tumor cells.
We have optimized the production of ONCAREX to an industrial level. Extensive test data and documentation exist on stability, PK, acute toxicology, maximum tolerated dose (MTD) and others. ONCAREX demonstrated efficiency against hepatocellular carcinoma and head & neck cancer in animal tumor models. We are currently preparing ONCAREX for clinical testing.