Research Focuses in Dr. Nghiem's Laboratory
1) UV-induced DNA damage responses and carcinogenesis in skin
One hour of sunlight (UV) exposure generates ~100,000 DNA lesions per cell, which are mutagenic. In response to UV, cells activate multiple biological processes (primarily via the ATR kinase) to cope with these deleterious lesions. However, chronic UV exposure leads to development of skin cancers, the most prevalent cancers in humans (annual incidence is 3.5 million in the US that exceeds all other cancers combined). Multiple human epidemiological studies showed that caffeine intake reduces the risk of developing skin cancers. We are elucidating the mechanism by which caffeine prevents skin cancers, leading to novel approaches to treat the most prevalent cancers.
2) Immunotherapy for Merkel cell carcinoma patients
Merkel cell carcinoma (MCC) is a rare but lethal skin cancer. In 2008, Merkel cell polyomavirus (MCPyV) was identified as the cause of MCC. The immune system is critical for suppressing this cancer; however, the immune response is often evaded in MCC patients. We are developing immunotherapy to restore the patient's immune response and effectively treat MCC.
My laboratory studies cell cycle control in normal and cancer
cells with an ultimate goal of discovering new approaches to prevent and treat
cancer. Our focus is a protein kinase called ATR that is required for the replication
checkpoint -- the means by which a cell ensures it does not undergo mitosis
before completely replicating its DNA. Our prior work has demonstrated that
loss of tumor suppressors such as p53 markedly sensitizes cells to death by
inhibition of ATR function.
We are using cell culture, transgenic mouse and chemical
genetic approaches to study:
View ATR animation
Updated Summary of Research Areas in the Lab:
There are two major areas of research in the Nghiem lab. The first is basic skin cancer biology focused on the replication checkpoint in cells. A particular interest is the molecular mechanism by which the protein kinase ATR mediates an essential cell cycle arrest following DNA damage such as by ultraviolet radiation. The second area involves basic, clinical and translational aspects of Merkel cell carcinoma, an uncommon, frequently lethal skin cancer associated with immune suppression, UV exposure and a newly describe polyomavirus.
Current effort on the replication checkpoint is centered on two topics. First, the lab studies the in vivo effects of ATR inhibition in the replication checkpoint by chemical and genetic approaches. While not specific, caffeine is a known inhibitor of ATR and has been shown to sensitize cells to premature chromatic condensation (a hallmark of ATR inhibition). Current studies use in vivo mouse models and suggest that caffeine's relevant target after UV is ATR. Second, the lab has screened several chemical libraries to identify small molecule inhibitors of ATR. Current studies include verifying specificity and mechanisms of these novel inhibitors.
Current effort on Merkel cell carcinoma has clinical, basic and translational components. Clinical studies of Merkel cell carcinoma (MCC) involve a longitudinal database of ~250 patients and analysis of prognostic factors for development of a staging system. Basic and translational studies include a genome-wide analysis of MCC genetics and the identification of a candidate oncogene (manuscript submitted). Further, the lab is investigating the role of the newly described "Merkel cell polyomavirus" in MCC pathogenesis.