Epithelial ovarian cancer is a deadly disease. The majority of patients with high-grade serous ovarian cancer (the most common subtype) initially respond well to a combination of surgery and platinum-based chemotherapy. However, most patients develop platinum-resistant tumors for which there are few therapeutic options and, consequently, most patients with high-grade serous ovarian cancer die of recurrent disease within a few short years of their initial diagnosis and so there is an urgent need for new therapeutic options to better treat drug resistant disease.
While it is known that the gene expression signatures (transcriptomes) of ovarian tumors are very different from those of the normal precursor cells, the transcription factor proteins that orchestrate these gene expression changes are largely unknown. We are particularly interested in identifying the master transcription factors regulating the core regulatory circuit of HGSOCs, as we expect these factors to play crucial roles in regulating tumor cell survival. The overarching idea underlying this research is that by characterizing the master transcription factors driving ovarian cancer development we can develop effective targeted therapies for the treatment of these aggressive tumors. We developed a novel algorithm which enabled us to leverage data from 10,000 tumors representing 33 tumor types to identify candidate master transcription factors for ovarian cancer. We have identified a strong candidate master transcription factor, named SOX17, which is expressed in ovarian cancers and in ovarian cancer precursor cells, but lowly expressed in other tumor types. We propose that SOX17 becomes deregulated during tumor progression and so we will use a combination of in vitro modeling, in vivo models and state-of-the-art genomics technologies (‘ChIP-seq’ and ‘RNA-seq’) to comprehensively evaluate the role of SOX17 in ovarian cancer development. By the end of this this project we will evaluate SOX17 as a much-needed novel therapeutic target for treating HGSOC.