David R. Bickers, M.D.
Dr. Bickers has devoted a major part of his research career to studying the role of cutaneous exposure to environmental carcinogens in the development of non-melanoma skin cancer. A major focus of the Bickers' laboratory over the last few years has been to develop a mechanism-based approach to skin cancer chemo prevention oncogenes and tumor suppressor genes. These studies have clearly shown that mutations in Ha ras oncogenes and in p53 in murine skin tumors, both benign papillomas and malignant squamous cell carcinomas, result from exposure of the skin to carcinogenic chemicals and ultraviolet B (UVB) radiation. More recently this work has been expanded to address the effect of UVB on the cell cycle in cultured human keratinocytes and in developing tumors in murine mouse models including heterogygous patched gene knockout mice. UVB induces p53 stabilization and activation in skin keratinocytes, which in turns induces the synthesis of p21, leading to inhibition of cdk2/cyclin E and cell cycle arrest at the G1/S transition. Dr. Bickers' results in skin keratinocytes lacking functional p53 show that UVB exposure result in the interruption of cell cycle progression in G1 phase by down regulating cyclin D and cdk4 levels and associated kinase activity. The down regulation of cyclin D and cdk4 levels is the result of UVB-mediated enhancement of proteosome-mediated degradation of protein kinase subunits. In addition, his laboratory observed an increase in cdk2-associated p27 following UVB treatment as down regulation of cdk4 releases p27 bound to cdk4/cyclin D complexes allowing the cki to bind and inhibit the activity of cdk2.
The Bickers Lab is also pursuing studies employing non-toxic inhibitors of cutaneous carcinogenesis. One such group of compounds is extracts of Japanese green tea and black tea. Polyphenol extracts from those materials have been shown to have potent anticarcinogenic effects in murine models and to substantially reduce the ability of UVB to trigger expression of early response genes that may be biological surrogate markers of UVB-induced carcinogenesis.
The laboratory has developed novel mouse models to study the effects of inhibition of ornithine decarboxylase (ODC) on skin carcinogenesis and to assess the effects of inhibitions of the sonic hedgehog pathway, such as, cyclopamine on this process. The laboratory is continuing to develop additional mouse models to study the pathogenesis of non-melanoma skin cancer.
More recently, Dr. Bickers and his group have established a major research collaboration with Dr. Ervin Epstein, Jr., M.D. at the University of California in San Francisco to study the photoprotective effect of Polyphenone E and cyclooxygenesis-2 (COX-2) inhibitors against UVB-induced and PUVA induced phototoxicity, UVB-induced carcinogenesis, PUVA-induced carcinogenesis in the skin of SKH-1 hairless and ptc +/- mice and UVB and PUVA-induced phototoxicity in human subjects. Part of this project also includes a human placebo-controlled double blind trial testing whether the Cox-2 inhibitor celecoxib can prevent the development of basal cell carcinomas in patients with a hereditary predisposition to develop such tumors – i.e., patients with the basal cell nevus syndrome.
Herbert Irving Pavilion
161 Fort Washington Avenue, 12th Floor
New York, NY 10032
Columbia Dermatology Associates
51 West 51st Street, Suite 390
New York, NY 10020