Cancer Metabolism

The therapeutic potential of targeting tryptophan catabolism in cancer

Abstract

Based on its effects on both tumour cell intrinsic malignant properties as well as anti-tumour immune responses, tryptophan catabolism has emerged as an important metabolic regulator of cancer progression. Three enzymes, indoleamine-2,3-dioxygenase 1 and 2 (IDO1/2) and tryptophan-2,3-dioxygenase (TDO2), catalyse the first step of the degradation of the essential amino acid tryptophan (Trp) to kynurenine (Kyn). The notion of inhibiting IDO1 using small-molecule inhibitors elicited high hopes of a positive impact in the field of immuno-oncology, by restoring anti-tumour immune responses and synergising with other immunotherapies such as immune checkpoint inhibition. However, clinical trials with IDO1 inhibitors have yielded disappointing results, hence raising many questions. This review will discuss strategies to target Trp-degrading enzymes and possible down-stream consequences of their inhibition. We aim to provide comprehensive background information on Trp catabolic enzymes as targets in immuno-oncology and their current state of development. Details of the clinical trials with IDO1 inhibitors, including patient stratification, possible effects of the inhibitors themselves, effects of pre-treatments and the therapies the inhibitors were combined with, are discussed and mechanisms proposed that might have compensated for IDO1 inhibition. Finally, alternative approaches are suggested to circumvent these problems.

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Author information

C.A.O., L.F.S.P., S.R.M., D.L.D., A.S., M.P. and S.T. collected literature, wrote, read, reviewed and revised the manuscript. L.F.S.P. and S.R.M. conceptualised and prepared the figures in the manuscript.

Correspondence to Christiane A. Opitz.

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Data availability

The data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) Project is publicly available.

Competing interests

C.A.O. and M.P. are listed as inventors on the patents “Means and methods for treating and/or preventing natural AHR ligand-dependent cancer” and “Isotopic method for measurement of tryptophan and metabolites thereof”. M.P. is listed on the patent “Treatment of Kynurenine-producing tumors with AHR antagonists”. M.P. has received research support and consulting honoraria from Bayer. The other authors have declared that no competing interests exist.

Funding information

This work was supported by grants from the BMBF e:Med initiative (GlioPATH, 01ZX1402) to S.T. and C.A.O. C.A.O. and A.S. were supported by funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 754688. L.F.S.P. was supported by scholarships from the University of Costa Rica (UCR) and Costa Rica’s Ministry of Science, Technology and Telecommunications (MICITT).

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Opitz, C.A., Somarribas Patterson, L.F., Mohapatra, S.R. et al. The therapeutic potential of targeting tryptophan catabolism in cancer. Br J Cancer 122, 30–44 (2020). https://doi.org/10.1038/s41416-019-0664-6

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