Targeting amino acid-metabolizing enzymes for cancer immunotherapy and treatment of Parkinson’s disease

Abstract

Metabolic homeostasis of amino acids is fundamental to human health and development. Accordingly, altered amino acid metabolism has been found to contribute to the pathogenesis of a variety of diseases, including cancer and Parkinson’s disease. In cancer, different amino acid-metabolizing enzymes are often aberrantly expressed, which promotes tumor growth and metastasis through suppression of the anti-tumor immune response. Amino acid-metabolizing enzymes therefore serve as promising immunotherapeutic targets for the treatment of various cancer types. An imbalance in tryptophan metabolism has additionally been associated with Parkinson’s disease, and inhibition of tryptophan-metabolizing enzymes is hence considered as a potential therapeutic strategy for its treatment. To date, however, no inhibitor of amino acid-metabolizing enzymes has yet been approved for treatment of either disease. Therefore, the research described in this thesis is aimed at contributing to the drug discovery process of inhibitors targeting these enzymes. In ovarian cancer patients, it is evaluated which amino acid-metabolizing enzymes may contribute to the pathogenesis of the disease, indicating IDO1 and IL4I1 as potential therapeutic targets for this specific cancer type. In addition, known inhibitors of the enzyme ARG1 are extensively characterized in this thesis, and an assay is developed to enable high-throughput screening of large compound libraries for inhibition of this enzyme. Finally, novel inhibitors of the enzymes IDO1 and TDO are evaluated in models of cancer and Parkinson’s disease, respectively. The main finding from these studies is that inhibitors of TDO not only reduce motor dysfunction in a murine model of Parkinson’s disease, but also improve non-motor symptoms of this disease. Overall, the work presented in this thesis is expected to contribute to the translation of these promising strategies into effective treatments for patients.