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Cyclin E1 as a Therapeutic Target in Women with High Grade Serous Ovarian Cancer and Primary Treatment Failure

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Technical Report,01 Sep 2015,31 Aug 2016

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University of Melbourne Parkville Australia

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A significant number of women with high-grade serous ovarian cancer HGSC are intrinsically refractory to standard platinum-based treatment. We have previously shown that amplification of the cyclin E1 gene CCNE1 in HGSC is associated with primary chemoresistance and poor clinical outcome. Therefore, we hypothesized that cyclin E1 is a key therapeutic target in HGSC, and that generation of a genetically engineered mouse GEM model of CCNE1-amplified HGSC will facilitate the development of novel therapeutic strategies. Here, we have generated two mouse strains with Cre-mediated expression of full-length or truncated Ccne1 at the Rosa26 locus. We plan to cross these mice with Pax8-TetOCre-Tp53 mice in order to induce expression of Ccne1 in the fallopian tube epithelium and drive the initiation and development of HGSC. Mouse models that closely resemble human disease have been powerful platforms for new therapies and understanding resistance mechanisms. Immune checkpoint inhibitors have shown substantial activity in melanoma and lung cancer, and it is now a priority to extend these findings to other solid cancers, including HGSC. The availability of an intact animal model ofCCNE1 is likely to be a substantial value in development of immune checkpoint inhibitors and other approaches to targetingCCNE1 amplified tumours.

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