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Current Landscape of NRF2 Biomarkers in Clinical Trials.

ABSTRACT: The transcription factor NF-E2 p45-related factor 2 (NRF2; encoded by NFE2L2) plays a critical role in the maintenance of cellular redox and metabolic homeostasis, as well as the regulation of inflammation and cellular detoxication pathways. The contribution of the NRF2 pathway to organismal homeostasis is seen in many studies using cell lines and animal models, raising intense attention towards targeting its clinical promise. Over the last three decades, an expanding number of clinical studies have examined NRF2 inducers targeting an ever-widening range of diseases. Full understanding of the pharmacokinetic and pharmacodynamic properties of drug candidates rely partly on the identification, validation, and use of biomarkers to optimize clinical applications. This review focuses on results from clinical trials with four agents known to target NRF2 signaling in preclinical studies (dimethyl fumarate, bardoxolone methyl, oltipraz, and sulforaphane), and evaluates the successes and limitations of biomarkers focused on expression of NRF2 target genes and others, inflammation and oxidative stress biomarkers, carcinogen metabolism and adduct biomarkers in unavoidably exposed populations, and targeted and untargeted metabolomics. While no biomarkers excel at defining pharmacodynamic actions in this setting, it is clear that these four lead clinical compounds do touch the NRF2 pathway in humans.

SUBMITTER: Yagishita Y

PROVIDER: S-EPMC7464243 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Current Landscape of NRF2 Biomarkers in Clinical Trials.

Yagishita Yoko Y Gatbonton-Schwager Tonibelle N TN McCallum Melissa L ML Kensler Thomas W TW

Antioxidants (Basel, Switzerland) 20200807 8

The transcription factor NF-E2 p45-related factor 2 (NRF2; encoded by <i>NFE2L2</i>) plays a critical role in the maintenance of cellular redox and metabolic homeostasis, as well as the regulation of inflammation and cellular detoxication pathways. The contribution of the NRF2 pathway to organismal homeostasis is seen in many studies using cell lines and animal models, raising intense attention towards targeting its clinical promise. Over the last three decades, an expanding number of clinical s ...[more]

PMID: 32784785

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Project description:IntroductionGlobal inequality in clinical research capacity and service delivery can be indicated simply by the proportion of clinical trials that a country or region has registered in clinical trial registry databases. The proportion of clinical trials registered in Africa is very low at 0.02%, even though the region accounts for approximately 15% of the world's population. Despite the economic challenges in most African countries, they have shown potential for growth and change in recent years.MethodsWe conducted desk reviews on the interventional clinical trials done in Kenya, Ethiopia, and Nigeria between 2015 to May 2023. The search was done in clinical trials repositories, and journal repositories. The search focused on intervention clinical trials. Data was extracted by screening through the publications and clinical trial platforms. The data extracted from the publications included the type of clinical trial, clinical trial phase, diseases, etc. The data extracted from the reports included: challenges in conducting clinical trials, capacity-building efforts, and the impact of the clinical trial.ResultsThe number of clinical trial studies identified in Kenya was 113 (28 were on infant clinical trials). The study identified 97 clinical trials in Nigeria, of which 11 studies were on infant clinical trials. In Ethiopia, there were 28 clinical trials and only five were on infant clinical trials. The landscape review also expanded to capacity and gaps in clinical trials in the three countries. The largest proportion of clinical trials carried out in Kenya was on injury, occupational disease, and poisoning, 30.5% (n = 18) and the smallest proportion was on kidney disease, neonatal disease, obstetrics, and gynecology. Most Infant clinical trials were carried out in the area of infections and infestations 33.3% (n = 7). Most of the challenges faced by clinical trials in the three countries include a lack of infrastructure, a lack of human resources, and a lack of financial resources.ImplicationsThere is a need to map clinical trials done by African researchers based in Africa to exclude the trials done by non-African researchers based in Africa. Opportunities for clinical trials should be supported and challenges addressed.

Dataset Information

Current Landscape of NRF2 Biomarkers in Clinical Trials.

Publications

Current Landscape of NRF2 Biomarkers in Clinical Trials.

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