Dr. Colven’s investigative interests include validation of store and forward telemedicine for dermatologic consultation and the impact of case-based learning on practice behavior.
Dr. Fleckman’s research focuses on the following: the pathophysiology of the ichthyoses, clinical aspects of nail disease. He created and maintains, together with scientists at Yale University, the National Registry for Ichthyosis and Related Disorders, a large reference database of individuals affected by ichthyosis which serves as a valuable resource for investigators of this disorder around the world.
Modulation of the replication checkpoint to combat UV carcinogenesis.
Ultraviolet (UV) from one-hour sunlight generates 100,000 DNA lesions per cell that are potentially mutagenic, leading to the most prevalent cancers in humans. Understanding how cells respond to UV-induced DNA lesions could be helpful to selectively kill DNA-damaged cells and prevent UV-associated skin cancers. Strikingly, multiple human epidemiological studies and mouse data demonstrated that caffeine suppresses UV-induced skin cancer development. We found that genetic inhibition of ATR, which is a pivotal kinase for surviving DNA damage, suppresses UV carcinogenesis, and this finding supports ATR inhibition as the relevant mechanism for the protective effect of caffeinated beverage intake.
Elucidation of mechanisms that respond to UV-induced DNA damage, especially ATR kinase pathway (replication checkpoint).
To better understand UV-induced DNA damage response, we recently dissected differential roles of two major types of UV-induced DNA lesions (cyclobutane pyrimidine dimers and 6-4 photoproducts) in ATR pathway activation and DNA replication blockage. This study provides insight into potential mechanisms by which caffeine inhibits mutation incorporation following UV irradiation.
Chemical genetic approach to discover novel small-molecule inhibitors of DNA damage response.
To discover druggable targets in the ATR pathway, we performed a phenotype-based screen of 9,195 small-molecule compounds and identified four compounds that inhibit the ATR pathway but are mechanistically distinct from typical ATR kinase catalytic inhibitors. This study highlights the complexity of the ATR pathway, and these novel ATR pathway inhibitors can be used to further elucidate druggable mechanisms in order to improve cancer therapy.
Dr. Nghiem’s research focuses on the biology, treatment and prevention of skin cancers. A major interest is in the biology and optimal therapy of Merkel cell carcinoma—a relatively rare, but often lethal form of skin cancer that is typically caused in part by a virus that is commonly on our normal skin, the Merkel cell polyomavirus. Dr. Nghiem's team has created a large data and specimen Repository for Merkel cell carcinoma to learn more about this challenging disease. The T lymphocyte immune response appears to play a central role in fighting this cancer and a key goal is to find effective means of stimulating relevant immune function in MCC patients. A second major interest is the role of the protein kinases ATR and Chk1 in the ‘replication checkpoint’--a key aspect of the response of cells to ultraviolet DNA damage. Caffeine intake is associated with decreased skin cancer rates and this appears to be via inhibiting the function of ATR (promoting death of pre-malignant/UV-damaged cells).
Dr. Raugi, following a three-year project funded by the Office of Rural Health to implement and evaluate a regional teledermatology program in VISN 20 (Northwest Network) of the VA, has received strong administrative and financial support to continue and expand teledermatology to include the regional urban centers. The pilot and feasibility project has become an independent Section in the Hospital and Specialty Service Line. While continuing to provide essential clinical services to Veterans in the Pacific Northwest, Dr. Raugi is continuing to develop and implement new evaluative methods for teledermatology services with the intent of improving the quality, timeliness, and effectiveness of Teledermatology care and improving the access to traditional dermatology services.
Dr. Shinohara established a multidisciplinary Clinic for Cutaneous Lymphomas at the Seattle Cancer Care Alliance in 2013. Her research interests include investigating the quality of life in patients with cutaneous lymphoma, and clinical trials investigating novel therapies for patients with cutaneous T-cell lymphoma.