High-grade serous ovarian carcinoma (HGSOC) is one of the most devastating cancer-related diseases in the United States. It is the deadliest gynecological malignancy and a public health burden. Historically, it was thought that ovarian tumors arise from the ovarian surface epithelium. Recently, this school of thought has been challenged by the finding of early HGSOC precursors in the fallopian tubes (FT) of women at increased risk of developing HGSOC due to mutations in the BRCA1 or BRCA2 genes. Most cases were localized to the fimbriated end of the FT and included serous tubal intraepithelial carcinoma (STIC) as the dominant precursor lesion. The Cancer Genome Atlas of HGSOC showed that approximately 50% of HGSOCs harbor mutations in the BRCA genes or other genes in the homologous recombination (HR) pathway of DNA repair. These tumors tend to respond well to chemotherapy and poly (ADP-ribose) polymerase (PARP) inhibitors. Unfortunately, the remaining 50% of HGSOC are often HR-proficient, do not respond well to standard treatment, and are associated with worse outcomes. HGSOCs with amplification of the CCNE1 gene represent a significant fraction of these HR-proficient tumors. CCNE1 makes a protein, cyclinE1, that controls cell division but which can also damage the cell's genome when present in excess. Women with CCNE1 amplified tumors are unlikely to respond to PARP inhibitors and thus represent an important unmet need. While there are a number of drugs currently in development in other solid cancers that may be effective in CCNE1 amplified HGSOC, there are currently no animal models to study the function of cyclin E1 in HGSOC or the efficacy of candidate inhibitors. This application describes our aim to develop a mouse model that mimics the human disease, thereby providing a preclinical platform for testing novel cyclinE1 inhibitors. We will construct transgenic mice where the Ccne1 gene can be precisely activated when and where we want it. Using well-established technology, we will engineer mice to express the cyclinE1 protein at high levels in FT secretory epithelial cells, the progenitors of HGSOC. We are very experienced in the generation of such animals and their analysis. Importantly, TP53 is always defective in human HGSC and its loss appears to be a requirement for cells to tolerate the presence of excess cyclinE1. Therefore, our model will incorporate expression of a mutant Tp53. Our laboratory studies suggest these two genetic alterations ? Ccne1 over expression and Tp53 mutation ? will be enough to generate tumors. It is also possible, however, that additional mutations will be needed for the mice to develop HGSC that mimic the human disease. In the second part of the grant we use data from a genetic screen in FT cells and information from thousands of cancer genomes to find genes that may cooperate with CCNE1 and that could be added to the mice. The study is likely to provide a high return on the invested effort, as the mice will provide an enduring resource - once the model is established it can be used in many settings, providing a powerful ongoing platform for development of CCNE1 inhibitors.
Ovarian cancer is the deadliest gynecologic cancer in the developed world. The proposed study will generate a mouse model of Ccne1-driven ovarian cancer that will provide insights into the pathogenesis of these tumors and serve as a platform for testing cyclinE1 inhibitors. We will also identify tumor suppressor genes that, when lost, cooperate with CCNE1 to drive neoplastic transformation.
