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Pathogenesis:
While there are many types of ovarian malignancies, high-grade serous carcinoma (HGSC) is the most common, aggressive, and lethal form. Recent work from our group and others suggests that a significant proportion of HGSCs arise from the fallopian tube epithelium (FTE) rather than from the surface of the ovary as previously thought. This new concept for serous tumorigenesis has led us to develop a number of novel model systems, including the ex-vivo model of benign FTE, the in-vitro fallopian tube secretory cell transformation model, a genetically-engineered mouse model that targets the FTE, and a series of primary patient-derived tumor xenograft models that retain the phenotypic and genotypic properties of the original patient tumors. By integrating findings from genomic studies into these model systems, we aim to define key factors that can lead to new therapeutics and methods of early detection.

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  Protein expression alterations along the morphological continuum from normal fallopian tube epithelial to high-grade serous carcinoma.

Cancer Genetics:
The post-TCGA (The Cancer Genome Atlas) landscape for high-grade serous ovarian carcinoma is marked by surprisingly few recurrent somatic mutations. Instead, this disease exhibits a complex genomic terrain marked by copy number alterations that are so widespread that few other cancer types mirror its complexity. The challenge now is to elucidate the alterations that are key players in tumorigenesis, tumor viability and chemotherapy resistance. Although mutations in the BRCA genes account for less than 10% of all HGSCs, dysfunction in the BRCA network and homologous recombination appears to be more widespread. Intriguingly, the TCGA analysis found that BRCA mutation and Cyclin E (CCNE1) gain are largely mutually exclusive, yet both BRCA1/2 dysfunction and CCNE1 amplification lead to wide-spread genomic instability and tumor progression. PARP inhibition has been shown to be synthetically lethal with BRCA1, while CCNE1 amplification is associated with primary treatment failure and poor outcome. We are now deploying whole genome screens in our in vitro and in vivo platforms to investigate the role of CCNE1 in early tumor progression and to define the circuitry of these tumors that might reveal new avenues for therapeutic intervention.

Early Detection:

There are currently no tools available for the early detection of ovarian cancer. Using a combination of FTE-derived ex-vivo models and highly refined mass spectrometry we are interrogating the secretome of malignant cells versus benign FTE cells. We have identified a number of candidate biomarkers, including HE4 and Elafin. Our prior work on HE4 showed that it was expressed and secreted as a glycoprotein by HGSCs. It was recently approved by the FDA for monitoring patients with HGSCs. Expression of Elafin is associated with poor overall survival and the protein exhibits mitogenic properties that likely underlie its association with poor outcome. Work in progress is aimed at defining the underlying mechanism of these effects.

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State of the Science in Ovarian Cancer Research--Meeting 2
Panel 1 Presentation: Ron Drapkin (16:37)
Panel presentation by Ron Drapkin, University of Pennsylvania

 


Research Discussion, SSC Executive Council Breakfast | Dana-Farber Cancer Institute



Bridge Project Events 2012
Understanding the Unmet Needs in Ovarian Cancer



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