MICA: A platform to support the pharmacological targeting of Nrf2 in humans

Oxidative stress is caused when there is an imbalance between harmful free radicals and protective antioxidants in the body. It is linked to many forms of human disease. Normally, cells respond to oxidative stress by increasing the activity of Nrf2, a protein that controls the expression of over 200 protective genes. Some of these genes help our cells to make more antioxidants and remove the harmful free radicals. This lowers levels of oxidative stress in the body. A large number of preclinical studies have shown a beneficial role of activating Nrf2 in different types of disease. In addition, a small number of drugs that stimulate Nrf2 have recently entered clinical trials. Despite these exciting advances, there remain two key knowledge gaps that prevent us from using Nrf2 activating drugs effectively in certain clinical settings, namely: 1. An uncertainty around whether using Nrf2 activating drugs to treat diseases that are known to increase a patient's risk of developing cancer could further promote tumour formation. This is linked to the fact that high levels of Nrf2 activity have been detected in many forms of cancer. 2. A lack of awareness about the best way to monitor the response of Nrf2 to drug stimulation in patients using samples such as blood. This is important as we need ways to confirm that a drug has stimulated Nrf2 in order to link this to any positive effects on a disease. This will help us to confirm that stimulating Nrf2 with drugs is a good strategy in patients. The aim of this fellowship is to use state-of-the-art cell, animal and clinical approaches to address these knowledge gaps and provide evidence to support the stimulation of Nrf2 as a novel approach to treating human diseases associated with oxidative stress. A good example of such a disease, and one in which Nrf2 is showing promise as a novel therapeutic target, is a form of fatty liver disease that affects over 5 million adults in the UK and currently lacks any approved therapies. Importantly, up to 20 % of patients with this disease will go on to develop primary liver cancer. In this fellowship, I will tackle the first knowledge gap by testing whether a drug that stimulates Nrf2 can improve the fatty liver disease and inhibit the development of primary liver cancer, or whether it can make the development of primary liver cancer worse. I will test whether the balance of these outcomes is affected by whether treatment with the drug is started in the early or advanced stages of fatty liver disease. The findings will also be important for other diseases in which Nrf2 appears to be a promising new drug target. These include certain lung and kidney conditions that involve oxidative stress, but which are also linked to an increased risk of developing cancer. I will tackle the second knowledge gap by measuring changes in all genes and proteins in samples of blood from patients and healthy volunteers taking drugs that stimulate Nrf2. I will look for gene/protein levels that change the most in response to the drugs when compared to normal levels, as these are likely to be markers of the Nrf2 response that will change in patients taking other Nrf2 activating drugs. In the long term, we will be able to develop specific tests of the Nrf2 response based on the measurement of these genes/proteins, and use these tests to better interpret the therapeutic effects of Nrf2 activating drugs in patients. Overall, this fellowship will improve our understanding of the benefits and risks of using drugs to stimulate Nrf2 in patients, and enhance our ability to monitor therapeutic responses in the clinic. This will support the development of new medicines in different forms of disease.