Several projects in Furdui’s laboratory focus on deciphering the redox mechanisms of disease with implications in prevention, diagnosis, treatment and improvement of patients quality of life. Two projects are briefly summarized here.
Lung Injury with Exposure to Environmental Stressors
At an organismal level, it is well known that infections, as well as dietary and environmental stressors (e.g., environmental toxins, nanoparticles and radiation) induce acute or chronic accumulation of reactive oxygen species (ROS) leading to disease. The consequence of exposure to radiation is determined by many parameters including the radiation source, radiation dosage (amount of radiation energy received), length of exposure and, importantly, the genetic and epigenetic makeup of the exposed individual. These parameters can range widely, and humans may be exposed to either repetitive low-dose radiation from commonly used diagnostic tools in medicine, such as X-ray and computed tomography (CT) scanning, or high doses of radiation, such as those generated by targeted radiation therapy or even nuclear disasters. Similarly, silver nanoparticles (AgNPs) are widely applied nanomaterials for both commercial and clinical biomedical applications, and their toxicity depends on factors such as particle size, shape, surface charge and capping agent. Both radiation and AgNP exposure lead to apoptotic and necrotic cell death through mechanisms that involve DNA damage and induction of oxidative stress.
In this project, Furdui’s laboratory investigates the synergy of interaction between radiation and AgNPs leading to lung injury and how this may vary with the age of exposed individual. A particular focus of this project is on the mechanisms of mitochondria-cell communication, one of the key technologies being the use of DCP-NEt2C for protein sulfenylation described under Chemical Probes. The investigations of ROS interaction with biological systems at multiple levels from individual cells to human interaction with the environment and back are critical to our ability to prevent, diagnose early and treat disease.
Head and Neck Cancer
Prevention and Diagnosis
HNC is a largely preventable disease with major etiologic factors being smoking, chewing tobacco, excessive alcohol consumption and infection with Human Papillomavirus (HPV). These agents induce ROS as a major mechanism of their carcinogenic potential. Studies have shown clear benefits of early detection in improving overall survival and patients’ quality of life as treatment of smaller tumors would have a better chance of sparing critical anatomical parts such as salivary glands and vocal cords. Unfortunately, although some tools exist for early detection of cancer, they have significant limitations and vary widely depending on the tumor site. No tools exist that can be applied uniformly for imaging of the entire upper aerodigestive system.
Furdui’s laboratory investigates the mechanisms leading to HNC development by focusing on the contribution of oral microbiota and infections with sexually transmitted pathogens. Development by this group of PET imaging agents targeting protein sulfenylation is also expected to greatly facilitate the early diagnosis of HNC.
Treatment
Radiation therapy is often used in treatment of HNC patients, typically in combination with surgery and/or chemotherapy. However, not all patients respond to treatment and even when there is response, the recurring tumors tend to be resistant to chemoradiation treatment. Currently, there is a lack of imaging methods to predict the patients most likely to benefit from radiation before the start of treatment.
Furdui’s group focuses on elucidating the molecular basis of resistance to radiation treatment, discovery of new radiation sensitizers and development of PET imaging tools to enable selection of patients most likely to benefit from radiation therapies. Studies for this project are performed using matched cell culture models of response to radiation treatment and clinical specimens from consented HNC patients undergoing treatment at our Medical Center. The data are combined with those from existing cancer databases such as the TCGA and others to derive new hypotheses, test and validate findings that would ultimately lead to better diagnosis and therapies for HNC patients.
Quality of Life
Owing to the location of the tumor, HNC patients often suffer from impairments in swallowing, breathing and speaking as side effects of radiation or chemoradiation therapy, greatly affecting their quality of life. Preventing and controlling these complications can not only improve the quality of life but also allow these patients to continue treatment, achieving overall better cancer management.
Furdui’s group focuses on the mechanisms by which antioxidants aid in treatment of xerostomia (dry mouth), a side effect of radiation therapy in HNC.
All projects are aided by numerous collaborators who provide critical clinical, technological and computational input to these projects.
Chen X., Mims J., Huang X., Singh N., Motea E., Planchon S.M., Beg M., Tsang A.W., Porosnicu M., Kemp M.L., Boothman D.A., Furdui C.M. (2017) “Modulators of redox metabolism in head and neck cancer.” Antioxid Redox Signal. Dec 20. [Epub ahead of print]
Lewis J.E., Costantini F., Mims J., Chen X., Furdui C.M., Boothman D.A., Kemp M.L. (2017) “Genome-scale modeling of NADPH-driven β-lapachone sensitization in head and neck squamous cell carcinoma.” Antioxid Redox Signal. Sep 14. [Epub ahead of print]
Chen X., Liu L., Mims J., Punska E.C., Williams K.E., Zhao W., Arcaro K.F., Tsang A.W., Zhou X., Furdui C.M. (2015) “Analysis of DNA methylation and gene expression in radiation-resistant head and neck tumors.” Epigenetics. Jun 3;10(6):545-61.
Mims J., Bansal N., Bharadwaj M.S., Chen X., Molina A.J., Tsang A.W., Furdui C.M. (2015) “Energy metabolism in a matched model of radiation resistance for head and neck squamous cell cancer.” Radiat Res. Mar;183(3):291-304.
Reisz J.A., Bansal N., Qian J., Zhao W., Furdui C.M. (2014) “Effects of ionizing radiation on biological molecules: Mechanisms of damage and emerging methods of detection.” Antioxid Redox Signal. Jul 10; 21(2):260-92.
Furdui C.M., (2014) “Ionizing radiation: Mechanisms and Therapeutics” Antioxid Redox Signal. Jul 10;21(2):218-20.
Bansal N., Mims J., Kuremsky J.G., Olex A.L., Zhao W., Yin L., Wani R., Qian J., Center B., Marrs G.S., Porosnicu M., Fetrow J.S., Tsang A.W., Furdui C.M. (2014) “Broad phenotypic changes associated with gain of radiation resistance in HNSCC.” Antioxid Redox Signal. Jul 10;21(2):221-36.
Glazer P.M., Grandis J., Powell S.N., Brown J.M., Helleday T., Bristow R., Powis G., Hill R.P., Le Q.T., Pelroy R., Mohla S., Bernhard E.J., DeGregori J., Ivan M., Vaezi A., Boothman D.A., Hammond E., Larner J., Wheeler D., Koumenis C., Chan D., Chen D., Czerniecki B.J., Dewhirst M., Furdui C.M., Lyden D., McBride W.H., Pajonk F., Powis G., Rich J., Haimovitz-Friedman A. (2011) “Radiation resistance in cancer therapy: meeting summary and research opportunities. Report of an NCI Workshop held September 1-3, 2010.” Radiat. Res. 176(3):e0016-21.