An interactive, interdisciplinary group will focus on the pathobiology of ovarian cancer at the genetic, molecular, cellular, and whole organism levels. 1) The first project will employ genome copy number and expression profiling by array CGH and expression array analysis to detect and localize recurrent genome copy number or gene expression changes and their association with histology, progression and clinical outcome; associations will be validated with tissue microarrays and 2) gene discovery using high-resolution array CGH to detect regions of recurrent genomic changes, comparative genomic sequencing to identify genes associated with narrowly defined regions, and analyzing functions of genes present at altered genome copy number and differentially expressed in human tumors. In the second project, based on the hypothesis that understanding mechanisms underlying production and action of LPA will improve understanding of tumorigenesis progression, and outcome and will lead to new diagnostic and therapeutic approaches, the role of LPA and its receptors in carcinogenesis will be characterized, the genes induced by LPA in ovarian cancer cells identified, and the possible use of LPA levels in detection and management assessed. The third project, based on the discovery of a putative novel tumor suppressor gene, ARHI, the clinical significance and mechanism of loss of ARHI expression in malignant ovarian epithelial cells, will be studied by determining: 1) effects of ARHI expression of proliferation, invasion, metastasis and survival of ovarian cancer cells, 2) mechanisms by which ARHI interferes with signal transduction; and 3) use of ARHI for gene therapy of ovarian cancer xenografts with our without cytotoxic drugs. In the fourth project, because of an increased copy number in PI3-K in 80% of ovarian cancers, the role of abnormalities in the PI3K pathway in pathogenesis, the effect of abnormalities in the PI3-K pathway on responsiveness to growth factors and, the mechanisms regulating signaling through the PI3-K cascade in ovarian cancer cells will be determined. The projects will be subserved by three cores: Administration, Biometry and Tissue/Pathology.
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