JAGUAHR Therapeutics is developing new immuno-oncology therapeutics targeting the AhR pathway.

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The Aryl Hydrocarbon Receptor (AhR) is a transcription factor that acts as a key regulator of the immune system. Endogenous ligands of the AhR include metabolic products of tryptophan (TRP) metabolism such as kynurenine, kynurenenic acid and cinnabarinic acid. The rate limiting step in the conversion of tryptophan to kynurenine is catalyzed by the enzymes IDO1, IDO2 or TDO. These are frequently overexpressed in numerous tumor types and convert tryptophan into kynurenine (KYN) which is then secreted into the tumor microenvironment (TME). Elevated IDO and TDO activity and KYN levels are associated with increased tumor grade and poor prognosis in many cancers.

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In the TME, KYN and other TRP metabolites, are actively transported into immune cells in which they activate the AhR leading to modulation of the immune system thereby inhibiting immune-mediated clearance of tumor cells. An antagonist of the AhR will reverse this tumor-derived immunomodulation and lead to restoration of immune-mediated killing of cancer cells. An additional advantage of targeting the TRP-KYN-AhR pathway via the AhR is that it is agnostic to whether KYN is produced by IDO1, IDO2 or TDO. Furthermore, the AhR is activated by other immunomodulatory ligands not derived from the TRP-KYN pathway, consequently an antagonist of the AhR may deliver greater efficacy than inhibitors IDO1, IDO2 and TDO. Finally, there is evidence that AhR expressed by tumor cells regulates key processes in tumorigenesis such as proliferation and migration, thus an AhR antagonist may have additional direct beneficial effects on cancer cells.  

In summary, the AhR represents a novel mechanism to treat cancer via a unique combination of immuno-oncology and direct anti-cancer effects.