): Prostate cancer is a major worldwide health problem. In the United States alone, an estimated 185,000 cases will be diagnosed in 1998, and nearly 40,000 men will die of disease. Although many prostate cancers eventually metastasize, the majority remain localized and clinically silent, posing significant dilemmas for patient management and public screening. The molecular basis of tumor initiation and progression in the prostate are poorly understood. Well-established oncogenes and tumor suppressor genes, such as MYC, RB1, and p53 are infrequently altered in prostate cancers. In addition, although cytogenetic and molecular data attest to the existence of multiple prostate tumor suppressor genes, most remain unidentified. Progress is further impeded by the lack of a prostate cancer animal model where the contribution of individual genetic lesions to the neoplastic phenotype can be explored. An understanding of the genetic changes underlying prostatic cancer would have a major impact on our ability to 1) identify individuals with a hereditary predisposition to prostate cancer, 2) predict which tumors will progress, and in the long term 3) design rational therapeutic modalities. We propose to develop the mouse as a model system for the identification and study of genes involved in prostate cancer. First, the cooperative phenotypic effects of two genes implicated in prostate cancer (Mxil and Pten) and their role in the growth and development of the prostate will be explored. These studies will serve as the foundation towards the development of a mouse model of prostate cancer that will serve as a tool for gene discovery. Lastly, these efforts will be complemented by a recently developed functional strategy for cloning tumor suppressor genes that circumvents laborious positional cloning techniques. The applicant is an M.D. who will have completed a residency in anatomic pathology with subspecialty training in the pathology of the reproductive tract prior to the proposed start date. He also holds a Ph.D. in genetics and developmental biology. The research will be carried out in a cancer biology laboratory within the Dana Farber Cancer Institute, an affiliate of the Harvard Medical School.
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