Cancer and the need for combined approaches to therapy
For long-term survival of cancer, treatments that target multiple cancer vulnerabilities and adapt to changes within the tumor may be required.
Activating the patients own immune system is an important part of such approach. The immune system is a powerful, flexible, and adaptive component for generating long-term remissions. However, chances of successful treatment may increase further if other aspects of cancer progression, like cancer stem cells, metastatic behaviour and reduced tumor cell apoptosis are be targeted simultaneously.
Blocking AhR holds the promise of a non-toxic therapy that targets multiple crucial tumor progressing processes at the same time.
AhR, hijacked to progress and sustain cancer
The aryl hydrocarbon receptor (AhR) is normally present in epithelial cells where it can be activated by various ligands. In normal tissues, AhR activity is involved in managing inflammation and metabolizing exogenous toxins. For example, Poly Aromatic Hydrocarbons (PAHs) are known activators of AhR.
In cancer tissue however, AhR is hijacked to act as direct mediator of tumor progression and a powerful inhibitor of tumor-specific immune responses. In the tumor microenvironment AhR seems to be mostly activated by tryptophan metabolites that are produced via IDO and TDO, the expression of which is upregulated in a positive feedback loop by AhR activation.
If activated, AhR translocates to the cell nucleus, where it causes the expression of many genes that are important to cancer progression.
Abnormally high levels of AhR are produced in many solid tumors, where AhR is constantly activated causing suppression of anti-tumor immune responses.
Apart from reducing the response of the immune system to cancer, AhR activation causes tumor cells to migrate, invade local tissue and metastasize to distant organs. The AhR also plays a role in producing “cancer stem cells”, a type of tumor cell that is highly resistant to chemotherapies and is thought to be responsible for lethal relapse and metastasis even years after “successful” chemo- or radiotherapy.
Activation of AhR in tumor cells
AhR is continuously activated in the tumor microenvironment by tryptophan metabolites like kynurenine, which are produced from tryptophan by the enzymes IDO and TDO. Tryptophan metabolites are upregulated via a positive AhR - IDO/TDO feedback loop in tumors, which further stimulates AhR activation.
Activation of AhR in components of the immune system
Many cells involved in immunity express AhR. Examples are macrophages, dendritic cells and T cells. Activation of AhR in immune cells, as a result of increased levels of AhR agonists in the tumor microenvironment, causes reduced anti-tumor immunity.
Hercules has developed HP163, a small molecule inhibitor of the AhR. By blocking AhR, Hercules' inhibitors not only boost anti-tumor immunity, they also suppress metastasis and the formation of chemo-resistant cancer stem cells. As such, HP163 has the potential to attack multiple vulnerabilities in the cancer microenvironment at the same time.
AhR inhibitors compared to IDO inhibitors