Therapeutic Strategies Against Cyclin E1 Amplified Ovarian Cancers
Technical Report,30 Sep 2015,29 Sep 2018
Dana-Farber Cancer Institute Boston United States
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Approximately 20 percent of high grade serous ovarian cancers harbor Cyclin E1 CCNE1 amplification and are associated with poor outcome and inferior responsiveness to standard platinum chemotherapy. Given their intrinsic resistance to platinum, management of CCNE1-amplified ovarian cancers is challenging. In this research, we evaluate three novel strategies against CCNE1-amplified ovarian cancers that address different aspects of CCNE1 biology. In the first aim, based on our preliminary data, we hypothesize that HSP90-inhibitors may be effective against CCNE1-amplified ovarian tumors because they suppress HR, downregulate BRCA1, and downregulate CCNE1. In the second aim, based on our preliminary data and the fact that RB functions downstream of cyclin E, we hypothesize that inhibition of FOXM1 and RB interaction is an effective approach for targeting CCNE1-amplified ovarian tumors. Specifically, suppression of FOXM1RB interaction will lead to enhancement of RBE2F interaction and suppression of E2F-dependent oncogenic activity resulting in activity against CCNE1-amplified cells. In the third aim, we hypothesize that miR-1255b, miR-148b, and miR-193b may be effective against CCNE1-amplified ovarian tumors in combination with platinum and PARPis. Potential mechanisms for this effect include suppression of HR and downregulation of BRCA1, RAD51 and BRCA2 that are relevant for CCNE1-amplified ovarian tumors which are dependent on hyperactive HR and are sensitive to suppression of BRCA1.
- Medicine and Medical Research