Lung cancer remains the leading cause of cancer deaths, and new therapeutic strategies are desperately needed. The Nrf2-Keap1-ARE pathway has been an attractive target for cancer prevention. Nrf2 activators prevent carcinogenesis in various preclinical models. However, more and more evidence suggests a tumor-promoting role of Nrf2 especially in lung cancer, and Nrf2 inhibitors are considered as candidates for cancer treatment. This dual role of the Nrf2 pathway focuses on the opposite effects on normal epithelial cells vs. tumor cells. However, the effects of Nrf2 on immune cells within the tumor microenvironment have not been fully investigated.
In Aim 1, my pre-doctoral training, I first characterized the immune signature in Nrf2 WT vs. KO mice during the process of carcinogenesis, and unexpectedly identified an unfavorable immune signature in Nrf2 KO tumors and lungs. Because of the contrasting effects on immune cells and tumor cells, I hypothesized that Nrf2 inhibitors will be ineffective for treating lung tumors in immune competent mice. To test this hypothesis, I identified a novel Nrf2 inhibitor through a high throughput screen and validated its activity in vitro. Further validation in vivo will be performed next, using standard models for testing Nrf2 inhibitors. Finally, the novel Nrf2 inhibitor will be tested for its ability to treat established tumors in immune-competent mice.
In Aim 2, the post-doctoral phase, I will extend my interest in exploring the interaction between tumor cells and the immune system. In particular, I would like to figure out which cell type and signaling pathways are compromising the response to immunotherapy in patients, and how we can best combine small molecule drugs with immunotherapy for a better clinical outcome.
Inhibition of the Nrf2-Keap1 pathway has become an attractive target for lung cancer treatment, since mutations in Nrf2, which are associated with chemoresistance and poor survival, have been found in lung cancer patients. However, there are no specific and potent Nrf2 inhibitors currently available, and the few compounds that have been reported as Nrf2 inhibitors have only been tested for treatment of tumors in xenograft models, which lack an intact immune system. In addition to identifying and developing a novel Nrf2 inhibitor, my research proposal tests the important question of whether Nrf2 inhibitors will be effective for treating tumors in immune-competent mice, which must be addressed before we consider inhibiting the Nrf2 pathway for treating lung cancer.
