What is the prospect of indoleamine 2,3-dioxygenase 1 inhibition in cancer? Extrapolation from the past
Open Access
- 8 February 2021
- journal article
- review article
- Published by Springer Science and Business Media LLC in Journal of Experimental & Clinical Cancer Research
- Vol. 40 (1), 1-14
- https://doi.org/10.1186/s13046-021-01847-4
Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1), a monomeric heme-containing enzyme, catalyzes the first and rate-limiting step in the kynurenine pathway of tryptophan metabolism, which plays an important role in immunity and neuronal function. Its implication in different pathophysiologic processes including cancer and neurodegenerative diseases has inspired the development of IDO1 inhibitors in the past decades. However, the negative results of the phase III clinical trial of the would-be first-in-class IDO1 inhibitor (epacadostat) in combination with an anti-PD1 antibody (pembrolizumab) in patients with advanced malignant melanoma call for a better understanding of the role of IDO1 inhibition. In this review, the current status of the clinical development of IDO1 inhibitors will be introduced and the key pre-clinical and clinical data of epacadostat will be summarized. Moreover, based on the cautionary notes obtained from the clinical readout of epacadostat, strategies for the identification of reliable predictive biomarkers and pharmacodynamic markers as well as for the selection of the tumor types to be treated with IDO1inhibitors will be discussed.Keywords
Funding Information
- Key Biomedical Program of Shanghai (18431902600)
- Key Biomedical Program of Shanghai (17431902200)
This publication has 126 references indexed in Scilit:
- IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: A novel IDO effector pathway targeted by D-1-methyl-tryptophanOncoImmunology, 2012
- Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenaseProceedings of the National Academy of Sciences of the United States of America, 2012
- Molecular Basis for the Substrate Stereoselectivity in Tryptophan DioxygenaseBiochemistry, 2011
- Indoleamine 2,3-Dioxygenase Expression in Human Cancers: Clinical and Immunologic PerspectivesClinical Cancer Research, 2011
- Hallmarks of Cancer: The Next GenerationCell, 2011
- Indoleamine 2,3-dioxygenase and 3-hydroxykynurenine modifications are found in the neuropathology of Alzheimer's diseaseRedox Report, 2010
- Expression of indoleamine 2,3-dioxygenase in nasopharyngeal carcinoma impairs the cytolytic function of peripheral blood lymphocytesBMC Cancer, 2009
- New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1)European Journal of Cancer, 2009
- Structure Based Development of Phenylimidazole-Derived Inhibitors of Indoleamine 2,3-DioxygenaseJournal of Medicinal Chemistry, 2008
- Indoleamine 2,3-dioxygenase is a novel prognostic indicator for endometrial cancerBritish Journal of Cancer, 2006