Aryl hydrocarbon Receptor (AHR) /
IDO Cancer

Amongst several factors that contribute to an immunosuppressive tumor environment, high levels of the tryptophan-degrading enzymes – IDO (Indoleamine 2,3-dioxygenase) and TDO (Tryptophan 2,3-dioxygenase) are outstanding. Both enzymes metabolize tryptophan into N-Formyl-kynurenine from which L-Kynurenine is formed. Kynurenine, Kynurenic acid (KA) and other secondary metabolites are endogenous activators of the Aryl hydrocarbon Receptor (AHR). AHR is a key orchestrator of the immune response and if activated by endogenous ligands like kynurenine and others, it can dampen the immune response in several cell types such as T-cells, myeloid cells, NK cells etc. This attenuation of the immune response is a natural homeostatic mechanism to prevent tissue damage, in particular in epithelial tissues such as the intestinal lining or the skin which are permanently exposed to pathogens such as bacteria and fungi.

From IDO inhibition towards AHR antagonisation

Cancer seems to hijack this mechanism by upregulating the Tryptophan-Kynurenine pathway through the overexpression of IDO, TDO, AHR or a combination of these three. IDO was first identified as an enzyme strongly correlating with an adverse outcome in cancer thus, many companies have developed IDO inhibitors. Despite initial positive results, the first IDO inhibitor in advanced clinical development, Epacadostat, failed to demonstrate benefits in a large-scale phase 3 trial in melanoma patients.

It was debated that this trial had several shortcomings but one straight-forward explanation is that tumors that overexpress TDO rather than IDO cannot be adequately targeted solely by IDO inhibitors.

This has been one of the reasons Phenex has decided to shift its research interests into the AHR pathway towards inhibiting AHR activation by antagonists, since AHR is clearly the downstream receptor of Kynurenine and its metabolites. First results from syngeneic mouse models with our AHR antagonists clearly show that this novel anti-tumor and immune-challenging mechanism has a stand-alone effect and can be combined with classical chemotherapy as well as immune checkpoint inhibitor therapy (Publications & Posters).

Phenex’ lead AHR antagonists show high potency, selectivity, favorable ADME/PK and are well tolerated, making them very attractive for clinical development.

References

See References

Brochez L, Chevolet I, Kruse V. The rationale of indoleamine 2,3-dioxygenase inhibition for cancer therapy. Eur. J. Cancer. 76:167-182. (2017).

Cheong JE, Sun L. Targeting the IDO1/TDO2-KYN-AhR Pathway for Cancer Immunotherapy – Challenges and Opportunities. Trends Pharmacol Sci. 39(3):307-325. (2018).

Gutiérrez-Vázquez C, Quintana FJ. Regulation of the Immune Response by the Aryl Hydrocarbon Receptor. Immunity. 48(1):19-33. (2018).

Munn DH, Mellor AL. IDO in the Tumor Microenvironment: Inflammation, Counter-Regulation, and Tolerance. Trends Immunol. 37(3):193-207. (2016).

Murray IA, Patterson AD, Perdew GH. Aryl hydrocarbon receptor ligands in cancer: friend and foe. Nat Rev Cancer. 14(12):801-14. (2014).

Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, Schumacher T, Jestaedt L, Schrenk D, Weller M, Jugold M, Guillemin GJ, Miller CL, Lutz C, Radlwimmer B, Lehmann I, von Deimling A, Wick W, Platten M. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature. 478(7368):197-203. (2011).

Platten M, von Knebel Doeberitz N, Oezen I, Wick W, Ochs K. Cancer immunotherapy by targeting IDO1/TDO and their downstream effectors. Front Immunol. 5:673. (2015).

Prendergast GC, Malachowski WP, DuHadaway JB, Muller AJ. Discovery of IDO1 Inhibitors: From Bench to Bedside. Cancer Res. 77(24):6795-6811. (2017).

Prendergast GC, Mondal A, Dey S, Laury-Kleintop LD, Muller AJ. Inflammatory Reprogramming with IDO1 Inhibitors: Turning Immunologically Unresponsive ‘Cold’ Tumors ‘Hot’. Trends Cancer. 4(1):38-58. (2018).

Rothhammer V, Quintana FJ.The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. Nat Rev Immunol. 19(3):184-197. (2019).

Sherr DH, Monti S. The role of the aryl hydrocarbon receptor in normal and malignant B cell development. Semin Immunopathol. 35(6):705-16. (2013).

Stockinger B, Di Meglio P, Gialitakis M, Duarte JH. The aryl hydrocarbon receptor: multitasking in the immune system. Annu Rev Immunol. 32:403-32. (2014).

Xue P, Fu J, Zhou Y1. The Aryl Hydrocarbon Receptor and Tumor Immunity. Frontiers in Immunology. 9:286. (2018).

AHR / IDO Cancer mode of action

OUR R&D PROGRAMS

LXR / NASH

Cancer Metabolism

AHR / IDO Cancer

About Phenex