Solid tissue malignancies are often detected at such an advanced stage that almost any therapy is doomed to failure. Therapy directed at early lesions should have a higher probability of success, but the early events in neoplastic progression occur sporadically and unpredictably. These early neoplastic cells are therefore difficult to investigate in humans. Designing effective strategies to eliminate cells in early stages of neoplastic progression is currently impossible because their fundamental characteristics are unknown. A large body of evidence now indicates that the generation of a malignant cell requires many genetic changes that would be improbable in a normal cell. Although it is often assumed that genomic instability develops only in association with defects in DNA repair pathways, several recent investigations have revealed multiple sources of genetic effort in the cell cycle itself. The goal of this proposal is to determine the properties of the genomically unstable and abnormally proliferating cell, which appears to be an early abnormality in the development of most, if not all, solid tissue neoplasms. The investigations will be performed in a transgenic mouse model in which cell cycle abnormalities and genomic instability develop in 100% of individuals at defined stages and in which they can be clearly related to the later formation of tumors. Only after the properties of these early neoplastic cells have been defined in such a model system can effective strategies to eliminate them be devised.
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