Whole Body Redox Maps for Metastatic Cancer Therapy

About This Grant

Project Summary Antioxidants have been widely believed to offer protection against cancer. However, landmark studies involving 35,000 men revealed the opposite: antioxidants such as vitamin E daily supplements, significantly increased, not decreased, the risk of developing prostate cancer (PC). At the Trotman Lab, we pioneered oxidative cell death therapy of PC: by giving the pro-oxidant menadione to mice with natively growing lethal PC we discovered that it affords a potent and durable therapeutic response. This is in contrast to castration therapy in RapidCaP and in men, which invariably is followed by relapse of disease. Menadione, a precursor of dietary vitamin K, selectively kills prostate cancer cells through triaptosis while sparing healthy tissues. At the same time standard of care (SOC) therapy interventions against PC such as radio- and radioligand therapy or chemotherapy are known to exert oxidative stress. However, we still lack cell level organ maps that inform us about (1) native redox states of tissues, (2) redox states of tumors and their metastases, and (3) if and how these redox states are changed by therapy. To satisfy this need, we here propose to expand on the rigorous approach, developed by the Lyons lab, of using the natural protein degradation based sensing of redox stress for in vivo visualization. The strategy uses ROS-dependent degradation of a red channel protein that reports the redox stress, while a green channel reporter serves as internal reference. With these reporters, we will generate two complementary native and immune competent animal models that reveal whole body redox maps of prostate cancer: OxiGEM will harbor the redox reporter in the germline in the Rosa26 locus so that organs reveal cell based redox states as red to green channel ratios (Aim 1). RoxyCaP will be based on RapidCaP, where virus based somatic gene transfer changes a single normal prostate cell into a tumor initiator but now it will also contain the redox reporter. This will allow us to reveal the cell level redox state of tumors during indolence and contrast it with escape and metastatic spread of the cancer. To visualize these models, we use 3 complementary state-of-the art whole organ imaging techniques that also ensure compatibility with molecular and -omics analyses of the results. Collectively, our models will yield a fundamental understanding of whether or not metastatic tumor progression and its therapy are dictated by redox states.