Translational Projects
Project 1: Epidemiology and Genetics of early onset Basal Cell Carcinoma
Susan Mayne, PhD and Allen Bale, MD/PhD, Co-Directors
This is an epidemiologic study of early onset (<40 years) basal cell carcinoma (BCC), with the goal of identifying environmental factors that may explain the apparent increase in incidence of this disease, especially in women, and to elucidate the genetic factors that may underlie early-onset, multiple tumors. In this study several possible risk factors for the disease are being evaluated on 500 controls and 500 cases of early-onset BCC including solar radiation, tanning bed use, cigarette smoking, obesity, genetic and other factors. The mutational spectrum in BCCs (frequency of UVB “signature” mutations vs. non-UVB) is correlated with the relevant environmental risk factors. The study will determine the proportion of known hereditary syndromes among individuals with early onset, multiple BCC, and the genetic basis for BCC predisposition among those without a known syndrome.
Project 2: Predictive and Therapeutic Utilities of Epigenetic Changes in Chromatin in Melanomas
Sherman Weissman, MD, Mario Sznol, MD and Ruth Halaban, PhD, Co-Directors
The overall goal of this project is to understand the role of epigenetics in melanoma genesis and regulation of growth and apoptosis. Epigenetic, such as DNA methylation, is a reversible process that is being harness in cancer therapy. DNA methyltrasnferase inhibitors, such as 5-Aza-2'-deoxy-cytidine (5-Aza-CdR) are in clinical trials for the treatment of cancer including melanoma. However, patients' responses are variable and there is a need for molecular markers that can predict and/or monitor the efficacy of therapy and can also suggest possible targets that can synergize with 5-Aza-CdR. In this project the investigators developed an approach for whole genome methylation analysis, utilized a whole-genome differential gene expression to identify pathways that can lead to growth arrest in response to 5-Aza-CdR, and identify agents that can induce growth arrest synergistically with 5-Aza-CdR. In addition, regions of DNA promoter methylation are being explored for the development of melanoma markers. Some of the results are published in Genome Research (Pelizzola, M., Koga, Y., Urban, A. E., Krauthammer, M., Weissman, S., Halaban, R., and Molinaro, A. M. 2008. MEDME: An experimental and analytical methodology for the estimation of DNA methylation levels based on microarray derived MeDIP-enrichment, Genome Research, in press).
Project 3: RAF-Kinase Targeted Therapy and Mechanism of Resistance
Ruth Halaban, PhD and Harriet Kluger, MD, Co-Directors
The general goals of this project are to test the efficacy of 10 Plexxikon novel RAF inhibitors on a panel of ~30 melanoma cell lines freshly isolated from individual tumors that are well characterized for known melanoma mutations, to investigate the molecular basis for primary and secondary resistance to the drugs, and to identify markers related to drug response and drug resistance. These studies are performed in collaboration with the YSPORE Bioinformatics Core that analyzes and integrates the data, surgeons, pathologists and oncologists that provide all the clinical information required to cluster the melanoma molecular signatures according to stage and response to current therapies. Working with these drugs while they are still in development will give us the advantage of being among the first sites in clinical trials that can benefit melanoma patients and designing rational correlative studies.Project 4: Serological Profiling of Melanoma Patients as a Diagnostic Tool
Ruth Halaban, PhD and Harriet Kluger, MD, Co-Directors
The major goal of this project is to identifiy markers in plasma or serum of melanoma patients. The plan is to develop melanoma-associated serological test composed of antibodies and antigens that can be used as the basis for a comprehensive, informative and clinically applicable screening of melanoma patients. Candidate antigens are determined from the extensive data available from gene expression analyses, and several antigens are being tested by ELISA assays. In addition, ProtoArrays composed of thousands of recombinant human proteins will be tested for serological immune-profiles in patient undergoing immunotherapy.
