Phase 1a/b open-label study of IK-175, an oral AHR inhibitor, alone and in combination with nivolumab in patients with locally advanced or metastatic solid tumors and urothelial carcinoma (original) (raw)
Related papers
2020
Background Indoleamine 2,3-dioxygenase-1 (IDO1) is a promising target for immunotherapy in bladder cancer (BC). IDO1 breaks-down tryptophan to generate kynurenine derivates, which may activate the aryl hydrocarbon receptor (AHR). AHR is an important target for carcinogens, but its association with BC progression was unknown. Two IDO1 inhibitors used in clinical trials are 1-methyl-D-tryptophan (MT) and INCB240360. Because MT is an aromatic hydrocarbon, it may be a ligand for AHR. We hypothesized that AHR could be associated with BC progression and that MT could activate AHR in BC. Methods BC patients (n = 165) were selected from the Gene Expression Omnibus database. A cutoff point for relative expression of AHR and cytochrome 450 enzymes (CYP1A1, CYP1A2, and CYP1B1; markers of AHR activation) was determined to compare with the grade, stage, and tumor progression. For in vitro experiments, RT4 (grade 1) and T24 (grade 3) BC cells were incubated with MT and INCB240360 to evaluate the ...
Aryl Hydrocarbon Receptor as an Anticancer Target: An Overview of Ten Years Odyssey
Molecules
Aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor belonging to the basic helix–loop–helix (bHLH)/per-Arnt-sim (PAS) superfamily, is traditionally known to mediate xenobiotic metabolism. It is activated by structurally diverse agonistic ligands and regulates complicated transcriptional processes through its canonical and non-canonical pathways in normal and malignant cells. Different classes of AhR ligands have been evaluated as anticancer agents in different cancer cells and exhibit efficiency, which has thrust AhR into the limelight as a promising molecular target. There is strong evidence demonstrating the anticancer potential of exogenous AhR agonists including synthetic, pharmaceutical, and natural compounds. In contrast, several reports have indicated inhibition of AhR activity by antagonistic ligands as a potential therapeutic strategy. Interestingly, similar AhR ligands exert variable anticancer or cancer-promoting potential in a cell- and tissue-specif...
Determining the role played by Aryl Hydrocarbon Receptor (AHR) in the colon carcinoma tumor model
2018
by Poonam Yakkundi University of the Pacific 2018 Aryl hydrocarbon receptor (AHR), commonly known as an environmental sensor involved in the metabolism and elimination of xenobiotic substances, is also an important modulator in the development and functioning of the immune system. AHR expression is varied in the T cell subsets with the highest expression in T-helper 17 and T regulatory cells. Work from many researchers has suggested that AHR can act as a tumor promoter or a tumor suppressor depending on the tumor type. Our goal is to understand the role played by AHR in MC38 syngeneic colon carcinoma tumor model. In the absence of AHR, MC38 tumor progresses by an increase in tumor associated macrophages (TAMs), M2 macrophages and a decrease in CD8a positive cytotoxic lymphocytes. Analysis of the intratumoral cytokines reveals a pro-inflammatory phenotype. This has been assessed by pharmacologic blocking of the receptor using CH223191 and in AHR deficient (AHR-/-) mice. Therefore AHR...
Aryl hydrocarbon receptor ligands in cancer: friend and foe
Nature Reviews Cancer, 2014
The aryl hydrocarbon receptor (AHR) is a member of the basic helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) subgroup of the bHLH superfamily of transcription factors and is the only member of this family known to be activated by ligands 1. AHR was discovered as the receptor that binds 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; also known as dioxin) with high affinity; this receptor is capable of sustained hyperactivation, resulting in a myriad of toxicological outcomes. The half-life of TCDD in humans is approximately 10 years owing to its inability to be metabolized to a polar derivative that can be excreted. These properties contribute to the potency of TCDD as a promoter of liver and skin carcinogenesis in rodents 2. After heterodimerization with the AHR nuclear translocator (ARNT), AHR can induce the transcription of several cytochrome P450 (CYP) enzymes that are important in the metabolism and bioactivation of carcinogens, particularly polycyclic aromatic hydrocarbons (FIG. 1). DNA microarray studies have established that AHR either directly or indirectly regulates a myriad of genes involved in a wide variety of biochemical pathways, including energy metabolism, lipid and cholesterol synthesis, xenobiotic metabolism and various transportation pathways 3. AHR-knockout mice have provided insights into the physiological role of AHR and have been useful for exploring the influence of AHR expression on susceptibility to carcinogens. AHR is now known to be involved in various cellular processes, such as the cell cycle, epithelial barrier function, cell migration and immune function.
Detrimental activation of AhR pathway in cancer: an overview of therapeutic strategies
Current Opinion in Immunology, 2021
Sustained transcriptional activation of the aryl hydrocarbon receptor (AhR) promotes tumour growth and impairs the immune defence, at least for cutaneous melanoma and glioma. AhR ligands are produced by the tumour microenvironment (TME) and by the tumour itself (intracrine). The recent identification of interleukin-4-induced-1 (IL4I1), a parallel pathway to indoleamine 2 3-dioxygenase 1 (IDO1)/ tryptophan 2,3-dioxygenase (TDO), and its ability to generate AhR ligands, confirms that a complete inhibition of AhR ligand production might be difficult to reach. Here, we have focused on recent discoveries explaining the large varieties of AhR ligands and the functional consequences in terms of cancer cell plasticity and consecutive therapy resistance. We also examined therapeutic strategies targeting the AhR signalling pathway and their possible adverse effects. Since the end of 2019, two phase I clinical trials have investigated the ability of the AhR antagonist to "reset" the immune system and resensitize the cancer cells to therapies by preventing their dedifferentiation. Highlights AhR is an ubiquitous transcription factor activated by a broad spectrum of endogenous and exogenous ligands. Sustained AhR activation promotes immune regulation, cell dedifferentiation and therapy resistance in several cancers. Targeting the AhR-signalling pathway might restore therapy efficiency. Evaluation of AhR activity in patients' plasma might be a potential associated companion biomarker. Manuscript A c c e p t e d M a n u s c r i p t •• This study demonstrates that under BRAF inhibitor pressure, a small sub-population of persister melanoma cell fuels the relapse due to an AhR suractivation. 43. Kobayashi A, Sogawa K, Fujii-Kuriyama Y: Cooperative interaction between AhR.Arnt and Sp1 for the drug-inducible expression of CYP1A1 gene.
Aryl-hydrocarbon receptor as a potential target for anticancer therapy
Biomeditsinskaya Khimiya, 2018
Aryl-hydrocarbon receptor (Aryl Hydrocarbon Receptor, AHR) is a ligand-dependent transcription factor, whose functions are related to xenobiotic detoxification, response to inflammation, and maintenance of tissue homeostasis. Recent investigations suggest that AHR also plays an important role in the processes of carcinogenesis. Increased expression of AHR is observed in several types of tumors and tumor cell lines. In addition, it turned out that the composition of pharmaceutical drugs used in oncotherapy includes some ligands AHR. These facts allow us to consider an aryl-hydrocarbon receptor as a potential target for anticancer therapy, especially for the treatment of severe cancers whose treatment options are very limited or do not exist at all. In this review the examples of AHR ligands' effect on tumor cell cultures and on model mice lines with AHR-dependent response are discussed.
Current Opinion in Toxicology, 2017
The aryl hydrocarbon receptor repressor (AhRR) was first described as a specific competitive repressor of aryl hydrocarbon receptor (AhR) activity based on its ability to dimerize with the AhR nuclear translocator (ARNT) and through direct competition of AhR/ARNT and AhRR/ ARNT complexes for binding to dioxin-responsive elements (DREs). Like AhR, AhRR belongs to the basic Helix-Loop-Helix/Per-ARNT-Sim (bHLH/PAS) protein family but lacks functional ligand-binding and transactivation domains. Transient transfection experiments with ARNT and AhRR mutants examining the inhibitory mechanism of AhRR suggested a more complex mechanism than the simple mechanism of negative feedback through sequestration of ARNT to regulate AhR signaling. Recently, AhRR has been shown to act as a tumor suppressor gene in several types of cancer cells. Furthermore, epidemiological studies have found epigenetic changes and silencing of AhRR associated with exposure to cigarette smoke and cancer development. Additional studies from our laboratories have demonstrated that AhRR represses other signaling pathways including NF-κB and is capable of regulating inflammatory responses. A better understanding of the regulatory mechanisms of AhRR in AhR signaling and adverse outcome pathways leading to deregulated inflammatory responses contributing to tumor promotion and other adverse health effects is expected from future studies. This review article summarizes the characteristics of AhRR as an inhibitor of AhR activity and highlights more recent findings pointing out the role of AhRR in inflammation and tumorigenesis.
Molecular Pharmacology, 2002
2-(4-Amino-3-methylphenyl) benzothiazole (NSC 674495; DF 203) demonstrates drug uptake and metabolism by tumor cells sensitive to the antiproliferative activity of the drug [J Med Chem 1999;42:4172-4184]. In insensitive cells, little metabolism occurs. Because CYP1A1 can metabolize DF 203, the aryl hydrocarbon receptor (AhR) may mediate drug action. We demonstrate here that DF 203 increases CYP1A1 and CYP1B1 transcription in sensitive MCF-7 cells, accompanied by AhR translocation to the nucleus, increase in xenobiotic-responsive element (XRE)-driven luciferase activity, and induction of protein/DNA complexes on the XRE sequence of the CYP1A1 promoter. MDA-MB-435 and PC3 cells, resistant to DF 203, did not show drug-induced CYP1A1 and CYP1B1 gene expression. AhR was observed to be constitutively localized in the nucleus, with no induction of XRE-driven luciferase activity in transiently transfected cells and weak or no induction of protein/DNA complexes on the XRE sequence of CYP1A1. Taken together, these data elucidate a novel basis for antitumor drug action: induction in sensitive cells of a metabolizing system for the drug itself. These results suggest that clarification of the basis for differential engagement of AhR-related signaling in different tumor cell types may aid in further preclinical development and perhaps early clinical studies.
The Aryl Hydrocarbon Receptor Is Constitutively Active in Advanced Prostate Cancer Cells
PLoS ONE, 2014
Background: Distant prostate cancers are commonly hormone refractory and exhibit increased growth no longer inhibited by androgen deprivation therapy. Understanding all molecular mechanisms contributing to uncontrolled growth is important to obtain effective treatment strategies for hormone refractory prostate cancers (HRPC). The aryl hydrocarbon receptor (AhR) affects a number of biological processes including cell growth and differentiation. Several studies have revealed that exogenous AhR ligands inhibit cellular proliferation but recent evidence suggests AhR may possess intrinsic functions that promote cellular proliferation in the absence of exogenous ligands. Methods/Results: qRT-PCR and western blot analysis was used to determine AhR mRNA and protein expression in hormone sensitive LNCaP cells as well as hormone refractory DU145, PC3 and PC3M prostate cancer cell lines. LNCaP cells express AhR mRNA and protein at a much lower level than the hormone refractory cell models. Cellular fractionation and immunocytochemistry revealed nuclear localization of AhR in the established hormone refractory cell lines while LNCaP cells are devoid of nuclear AhR protein. qRT-PCR analysis used to assess basal CYP1B1 levels and a xenobiotic responsive element binding assay confirmed ligand independent transcriptional activity of AhR in DU145, PC3 and PC3M cells. Basal CYP1B1 levels were decreased by treatment with specific AhR inhibitor, CH223191. An in vitro growth assay revealed that CH223191 inhibited growth of DU145, PC3 and PC3M cells in an androgen depleted environment. Immunohistochemical staining of prostate cancer tissues revealed increased nuclear localization of AhR in grade 2 and grade 3 cancers compared to the well differentiated grade 1 cancers. Conclusions: Together, these results show that AhR is constitutively active in advanced prostate cancer cell lines that model hormone refractory prostate cancer. Chemical ablation of AhR signaling can reduce the growth of advanced prostate cancer cells, an effect not achieved with androgen receptor inhibitors or growth in androgen depleted media.