Despite advances in cancer biology, drug resistance is a major obstacle to patients and clinicians. Many current
cancer therapeutics work in part by elevating reactive oxygen species (ROS) production, often leading to tumor
regression followed by tumor reoccurrence and therapeutic resistance. Previously, Kelkka and coworkers looked
at tumor progression in mice with macrophages deficient in ROS from the protein NOX2 (Kelkka et al., 2013).
They concluded that immune cells are more efficacious against metastasis and tumor progression when ROS
production in macrophages is inhibited. On the other hand, others have demonstrated the relationship between
carcinogenesis and our innate antioxidant systems such as the thioredoxin reductase (TrxR) system and the
glutathione reductase system (Gorrini et al., 2013). As carcinogenesis progress, cells produce increasing levels
of ROS. Tumor cells cope with high levels ROS via an adaptive antioxidant response such as the thioredoxin
reductase system. However, when this system is impaired within tumor cells, in vivo tumor progression and
metastasis may be significantly inhibited (Yoo et al., 2006).
Given these findings, we believe that tumor cells become resistant to current therapies in part by the systemic
increase of ROS production, which 1) is insufficient to promote cell death in tumor cells because of their adaptive
antioxidant response, and 2) elevated levels of ROS impairs immune cells from effectively combating tumor cells.
Therefore we propose that a combined approach is required for effective anticancer therapy. We hypothesize
that tumor cells with dysfunctional antioxidant systems will significantly regress and that the host’s immune
response, under low ROS conditions, will be primed to eradicate the remaining malignancy.
The focus of this proposed PhD project is to investigate this hypothesis and characterize the optimal Redox
conditions for tumor regression. We plan to accomplish this using two well-established murine tumor models: 1)
the metastatic B16F10 melanoma and 2) the metastatic Lewis Lung Carcinoma, LLC1. We will characterize in
vitro the baseline Redox systems in these tumor models, make alterations using siRNA or CRISPR. We will also
look at tumor progression in living hosts. We will use six mouse strains to help us understand the significance of
host Redox biology, in both the immune cells and systemically, in response to cancer. Specifically, we will use
mouse models with key phenotypes: B6.129P2-Txnrd1tm1Marc, B6.129P2-Txnrd1Cond, BQ.Ncf1m1J (Ncf1 mutant
mice), BQ.Ncf4 (Ncf4 mutant mice), BQMN (expressing Ncf1 in macrophages only) and BQ.TN3
conditional knock-in mice. Finally, we will study tumor redox systems challenged with Auranofin and other