AhR Biology

The aryl hydrocarbon receptor (AhR) is a transcription factor that is activated by a variety of small molecules from various external and internal sources, such as diet and metabolic degradation products, microorganisms and pollutants.  Ligand binding triggers conformational changes in AhR that expose its nuclear localization signal, leading to AhR translocation to the nucleus where it controls the transcription of a wide variety of target genes.

AhR and Metastatic Breast Cancer

Aryl Hydrocarbon Receptor (AhR) affects signaling pathways critical to cell survival, proliferation and differentiation.   AhR mediates all major steps of cancer development – initiation, promotion, progression and metastasis.  In breast cancers AhR modulates Estrogen Receptor signaling in ER-positive breast cancers and affects growth of ER-negative and triple negative breast cancers.  It has been shown that treatment with AhR modulators inhibits the motility and invasion ability of highly invasive breast cancer cells, preventing metastasis.  Modulation of the AhR pathway in metastatic breast cancer also increases the efficacy of Chemo- and Radiation therapy.

AhR and Immuno-Oncology

The use of the PD-1 (programmed cell death receptor 1) antibodies in clinic, such as Keytruda® and Opdivo®, has produced some spectacular responses in patients with a broad spectrum of cancers. PD-1 protein is expressed on the surface of the immune cells, such as CD8+ T cells, during T cell activation.  PD-1 is an immune checkpoint that prevents the cytotoxic T lymphocytes (CTLs) from attacking the body’s own tissues.  Cancer cells commonly over-express PD-L1 ligand, which binds to the PD-1 receptor and blocks the ability of tumor-infiltrating CD8+ T cells to recognize and eliminate cancer cells.

Although the anti-PD-1 immunotherapy produced significant durable responses in some patients, the limitation of this approach is highlighted by low response rates and serious side effects.  In addition, some patients who initially respond to the anti-PD-1 therapy, still relapse after a certain period of time.

Recently, Aryl Hydrocarbon Receptor has been implicated in PD-1 upregulation in tumor specific cytotoxic CD8+ T cells through a transcellular kynurenine (Kyn)-aryl hydrocarbon receptor (AhR) pathway.

Cancer cells typically over-express indoleamine-2,3-dioxygenases 1 and 2 (IDO-1/2) and tryptophan-2,3-dioxygenase (TDO) enzymes responsible for tryptophan catabolism and its conversion into kynurenine, one of the several metabolic products.  Kynurenine is an endogenous AhR ligand.  It binds to the AhR with an apparent Kd of ~ 4 uM and acts as an agonist.  Upon binding kynurenine, AhR translocates to the nucleus where it controls the transcription of a wide variety of target genes.   Kynurenine inhibits proliferation of CD4+ and CD8+ T cells in a concentration-dependent manner, thus suppressing antitumor immune responses.  Profound suppression of cellular and humoral immune responses results in promotion of carcinogenesis and induction of tumor growth.

A self-renewing, highly tumorigenic subpopulation of cancer cells (cancer stem cells) has been shown to release kynurenine into tumor microenvironment upon IFN-γ stimulation.  Kynurenine is then taken up by neighboring tumor-infiltrating T cells via active transport.   In CD8+ T cells kynurenine upregulates PD-1 expression through induction and activation of AhR.

A strong correlation between Kynurenine levels and high PD-1 expression on tumor-infiltrating CD8+ T cells was observed in tumor tissues of breast and colon cancer patients. Thus, small molecules capable of competing with kynurenine for binding to AhR and modulating its activity represent a novel approach for the anti-PD-1 therapy.

Selective Aryl Hydrocarbon Receptor Modulators (SAhRM)

Actavalon has generated a series of highly potent small molecule selective Aryl Hydrocarbon Receptor Modulators (SAhRM) with either agonist, partial agonist or antagonist activities. In vivo, our SAhRM demonstrate significant tumor growth inhibition in mouse xenograft models with Triple Negative Breast Cancer (TNBC).  In vitro, our AhR antagonists potently inhibit AhR-driven expression of CYP1A1 and CYP1B1 in human cells.