NIH funded research in my laboratory investigates mechanisms of how cells sense cytoplasmic ionization events and modulate either pro- or anti-survival mechanisms. These studies have shown that in tumor epithelial cells or in normal cells under conditions of chronic inflammation, nitric oxide synthases (NOS) generate not only NO but other reactive nitrogen/oxygen species (RNS/ROS) that can selectively nitrate specific Tyrs of critical signaling proteins, such as p53, IkB, PKC and PP2A, resulting in changes in their activities and expression levels. These studies focus not only on tumors but also on normal tissue damage. Besides modern cell and molecular biological approaches, these studies have employed mass spectroscopy to analyze changes in the proteome of irradiated tissues and post-translational modifications of proteins, HPLC purification of key metabolites, structural modeling of proteins, and analysis of tumor cell growth in tissue culture, tumor xenografts and two models of spontaneous tumors. Animal studies have used animal survival, ex vivo clonogenic assay and PET/CT to monitor tumor growth and semi-quantitative IHC methods to analyze tumor hypoxia, tumor blood flow, protein expression and post-translational modification and tissue damage. More recently, we have used multispectral photoacoustic tomography to follow blood flow and oxygenation in both tumors and normal tissues prior to and post-radiation. A small animal, CT-based irradiator purchased through an NIH S10 grant facilitates 3D radiotherapy treatment of small animals. More recently, I was a co-PI on an internal proposal that was funded to purchase a small animal endoscope. My laboratory also collects blood from all consenting patients in our department in two IRB approved cancer studies with patients donating blood before, during, and after therapy, at 6 months post therapy and thereafter on an annual basis. We used the buffy coat DNA from these patients for a SNP analysis of key genes involved in endothelial function and fibrosis as potential predictors of late toxicities. We are using exosomes isolated from the plasma samples from prostate, lung and head and neck cancer patients to determine their role in modifying the tumor microenvironment (e.g. immune suppression and fibroblast proliferation) and how this changes during treatment. These plasma samples are also being analyzed for potential biomarkers of late toxicities.
Radiation, endothelial dysfunction, fibrosis, nitric oxide synthase, inflammation