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Department of Pharmacology
Jeffrey Field, Ph.D.

Education:

1980	B.A. (Biology)	Columbia University
1985	Ph.D. (Molecular Biology)	Albert Einstein College of Medicine

Research Summary:
Mutations in a group of genes called oncogenes lead to the uncontrolled growth that is the hallmark of cancer. Oncogenes express proteins that regulate signaling pathways essential to the tumor cell. Over the last few years oncogenes have emerged as bona fide drug targets with some of the newest anti-neoplastic drugs targeting them. Examples of newly approved drugs include Gleevec, Iressa and Herceptin. Identifying the key oncogene signaling pathways will ultimately lead to novel targets for pharmacological intervention.

A long term interest in the lab is the Ras oncogene, one of the most commonly mutated oncogenes as well as one of the most highly conserved signaling proteins. Mutational activation of Ras causes changes in three basic properties of cells. These are: (1) increases in cell proliferation to stimulate growth, (2) reorganization of the actin cytoskeleton to promote invasion and metastases and (3) inhibition of apoptosis to prevent tumor cells from undergoing programmed cell death. We have traced a new Ras signaling pathway to a protein kinase called Pak.

Our approach has been to integrate mechanistic studies of the signals from Ras to Pak with cell culture studies to determine the role of Pak in Ras biology. Perhaps most striking is our observation that inhibition of Pak in laboratory scale experiments reverts tumor cells. This is mediated by direct interactions between Pak and components of the classical Ras MAP kinase cascade. Pak also promotes cell survival by inhibiting apoptosis through interactions with other cell survival proteins, including Akt and Bad.

Our studies took the first steps towards validating Pak as a drug target and, in fact, a number of companies are now screening for Pak inhibitors. Ongoing studies are designed to pinpoint the signals from Ras through Pak and to develop models of the various cancers that may respond to Pak. To date we have shown a role for Pak in Neurofibromatosis associated tumors and HIV associated malignancies.

Another project in the lab approach exploits the Ras signaling system in the yeast Saccharomyces cerevisiae. Yeast RAS is 90% homologous to human Ras and remarkably, the yeast and human homologs are functionally interchangeable. We have a long term project studying yeast Ras signaling proteins and their mammalian counterparts.

A third area of interest in the lab has been to develop models for lung cancer mutagenesis. Poly cyclic aromatic hydrocarbons are among the most potent carcinogens in cigarette smoke. We have been modeling their mutagenesis of the p53 oncogene in a yeast system. This oncogene carries a unique signature in lung cancers and we have devised mutagenesis systems to model this signature.

These studies will enhance our understanding of Ras signaling by tracing the downstream signaling pathways that sustain cell transformation.