Redox modulation - Impact on Tumor Growth and Therapeutic Anticancer Efficacy

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PROJECT SUMMARY Despite advances in cancer biology, drug resistance is a major obstacle to patients and clinicians. Many cancer therapeutics elevate reactive oxygen species (ROS) production, often leading to regression followed by reoccurrence and therapeutic resistance. This project continues work published by Kelkka et al. which observed tumor growth inhibition in mice carrying a loss of function mutation in the Ncf1 molecule of the Nox2 complex (Kelkka, T. et al. 2013). Given that Ncf1 mutant mice are more susceptible to animal models of human autoimmune diseases (Zhong, J. et al. 2018), immune cells may be more efficacious against metastasis and tumor progression when ROS production in leukocytes is inhibited. However, their studies did not identify which leukocyte plays the major role in the Nox2-mediated tumor growth, presenting possible targets for cancer therapy. Currently five clinical trials are evaluating Auranofin, an FDA approved thioredoxin reductase 1 (TrxR) inhibitor, as a possible treatment for malignancies such as glioblastoma, ovarian cancer, lung carcinoma, and leukemia. Earlier studies have shown that inhibition of TrxR in tumors suppresses, in vivo tumor progression (Stafford, W. C. et al. 2018, Yoo, M. H. et al. 2006). However, these studies, and a vast majority of studies to-date, have limited testing of Auranofin to immuno-compromised animal models. We have strong evidence that TrxR inhibition in immune-competent animals significantly promote tumor growth of solid murine syngeneic tumors such as the B16F10 melanoma and the Lewis Lung Carcinoma (LLC) models. Our studies are supported by overlooked, yet convincing studies in the literature (Hiramoto, K. et al. 2014, Mirabelli, C. K. et al. 1985). Therefore, we also aim to show that inhibition of TrxR in dendritic cells or B cells may promote tumor progression. This reorganized PhD project, having been heavily affected by COVID due to dependence on multiple breeding, will finalize experiments for two high-impact manuscripts for publication aimed at journals such as Cell or Immunity: 1) A manuscript establishing the therapeutic potential of targeting Ncf1-Nox2 in syngeneic dendritic cells for use against B16F10 and LLC cancer models; 2) a manuscript establishing the effects of TrxR1 inhibition in dendritic cells and mechanism for promoting B16F10 and LLC tumor growth, and its implication for anticancer therapy. We will use six mouse strains to help us understand the significance of host Redox biology in cancer immune surveillance. Specifically, we will use mouse models with key phenotypes: BQ.Txnrd1Flox, BQ.Ncf1m1J (Ncf1 mutant mice), BQ.CD11c-cre, BQ.MB1-cre, BQ.CD4-cre, and BQ.TN3 conditional Ncf1 wildtype knock- in mice. If successful, this will be of therapeutic significance.