Tryptophan is an essential amino acid which is metabolized into catabolites necessary for physiological homeostasis. Of the various catabolic fates of tryptophan, the kynurenine pathway is of both basic and clinical interests due to its signature catabolite kynurenine which contributes to immune privilege, is a precursor of NAD +, and acts as an activating ligand of the transcription factor aryl hydrocarbon receptor (AHR.) Through elevated expression of tryptophan transporters and tryptophan-catabolizing enzymes, cancer cells promote the production of kynurenine and downstream catabolites. Oncogene-mediated upregulation of tryptophan transporters and tryptophan catabolizing enzymes IDO1, TDO2, and arylformamidase (AFMID) occur in several cancer types including breast, esophageal, liver, and colon cancers with correlation to poor prognosis. Targeting of the kynurenine pathway has therefore been a clinical focus; however, all initial clinical trials aiming to inhibit IDO1 failed. A new generation of clinical trials targeting IDO1, TDO2, and tryptophan transporters are underway, yet no preclinical evaluation of the enzyme (AFMID) has ever been conducted. AFMID acts immediately downstream of IDO1, IDO2, and TDO2 to catalyze the reaction that produces kynurenine itself. Unlike IDO1/2 and TDO2 which are functionally redundant, AFMID features a unique function. Despite its importance, no studies have comprehensively evaluated AFMID’s direct roles in metabolic reprogramming, cell-autonomous proliferation, or microenvironment remodeling. We aim to investigate the cell autonomous and immune modulatory functions of AFMID in colon cancer and to define novel approaches to inhibit AFMID activity as strategy to block the kynurenine pathway.
Support or Funding Information
Welch I-2058-20210327, NCI R01CA245548, American Cancer Society IRG-17-174-13 pilot grant, and University of Texas Southwestern Circle of Friends Early Investigator Award to MCS, and training grant 5T32GM131945-02
Tryptophan metabolism is a physiologically necessary process that is frequently aberrantly regulated in cancers. Through the metabolites of the kynurenine pathway, cancer cells gain the ability to contribute toward tumor progression via pro-proliferative transcriptomic changes and pro-tumoral immunosuppression.
