Mini-review: Limitations and Off-Target Effects of Tryptophan-Related IDO Inhibitors in Cancer Treatment, 2019, Gunther et al

[Andy]

Immunooncology is still a growing area in cancer therapy. Drugs within this therapeutic approach do not directly target/attack the tumor but interfere with immune checkpoints and target or reprogram key metabolic pathways critical for anti-cancer immune defense. Indolamine 2,3-dioxygenase 1 (IDO1) and the tryptophan (TRP)-kynurenine pathway were identified as critical mechanisms in cancer immune escape and their inhibition as an approach with promising therapeutic potential. Particularly, a multitude of IDO1 inhibiting tryptophan analogs are widely applied in several clinical trials. However, this therapy results in a variety of implications for the patient's physiology. This is not only due to the inhibition of an enzyme important in almost every organ and tissue in the body but also because of the general nature of the inhibitor as an analog of a proteinogenic amino acid as well as the initiation of cellular detoxification known to affect inflammatory pathways. In this review we provide a deeper insight into the physiological consequences of an IDO1 inhibiting therapy based on TRP related molecules. We discuss potential side and off-target effects that contribute to the interpretation of unexpected positive as well as negative results of ongoing or discontinued clinical studies while we also highlight the potential of these inhibitors independent of the IDO1 signaling pathway.

https://www.frontiersin.org/articles/10.3389/fimmu.2019.01801/full

 

[wigglethemouse]

Tagging @RDP - might be of interest

 

[Hoopoe]

As far as I understand:

What is happening with kynurenine and cancer cells with mutations that lead to a highly active kynurenine pathway can escape destruction by the immune system because activation of the kynurenine pathway has a local immunusuppressive effect.

There are attempts to develop drugs to suppress the activation of kynurenine pathway. It doesn't have anything to do with the metabolic trap hypothesis (which leads to an impairment of the kynurenine pathway).

 

[RDP]

https://www.frontiersin.org/articles/10.3389/fimmu.2019.01801/full

The field of IDO1 inhibitors and cancer has been hot for years now, but as this Frontiers article highlights, most Pharma firms abandoned these programs with the first Phase 3 failure.

I was actually glad these drugs did not meet their clinical endpoint goals because I worried that they might cure cancer, but CAUSE ME/CFS if the IDO trap hypothesis is correct.

One of the valuable side products of this enormous effort by Pharma is that it produced vastly more research on IDO1 that we can draw on in the context of the trap. I'll talk about some of these benefits in the last few slides of my upcoming talk at the Stanford Symposium.