Development of an Nrf2 inhibitor for the treatment of Nrf2-addicted cancer
| Project/Area Number |
19K16512
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 48040:Medical biochemistry-related
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| Research Institution | Tohoku University |
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Principal Investigator |
Baird Liam 東北大学, 医学系研究科, 助教 (90724914)
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| Project Period (FY) |
2019-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | Keap1-Nrf2 / synthetic lethal / Keap1 / Nrf2 |
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| Outline of Research at the Start |
Mutations in the Keap1-Nrf2 pathway are common events in human cancers, however there are currently no specific treatment options for tumors with activated Nrf2 signaling. Therefore, the purpose of this research is to identify compounds which function to specifically kill Nrf2-dependent tumors.
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| Outline of Final Research Achievements |
Activation of the KEAP-NRF2 pathway is observed in approximately 30% of human lung tumours, where it is associated with a poor prognosis and reduced overall survival for patients. Despite the fact that NRF2 is a validated driver of aggressive cancer growth, the complete lack of approved drugs which can target oncogenic NRF2 signaling means that there is an urgent clinical need to identify compounds which display efficacy against NRF2-dependent tumours. In this project, I developed a novel assay to identify compounds which could selectively kill tumour cells with high levels of NRF2 activity. Using this approach, I identified two different classes of compounds, geldanamycin-derived HSP90 inhibitors, and the DNA damaging agent mitomycin C, which both displayed NRF2-dependent toxicity.
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| Academic Significance and Societal Importance of the Research Achievements |
As there are no approved drugs which can be used to treat patients with NRF2-dependent tumours, there is an urgent unmet clinical need to identify such drugs. In this project, I identified the chemotherapy drug mitomycin C to be an ideal candidate for drug repositioning to NRF2-dependent tumours.
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Report
(3 results)
Research Products
(3 results)
