Therapeutic Strategies against Cyclin E1-Amplified Ovarian Cancers
Abstract
Approximately 20% of women with ovarian cancer have tumors that harbor a specific genetic change called "Cyclin E1 (CCNE1) amplification." In these tumors, the CCNE1 gene is present in multiple copies, i.e., it is expressed in much higher-than-normal levels. Patients with such tumors do not respond well to standard platinum-based chemotherapy, and their overall survival is unfortunately poor. One of the reasons for this is that, unlike other ovarian cancers, ovarian tumors with CCNE1 amplification can promptly repair the damage caused by chemotherapy and are therefore not killed effectively by chemotherapy. Furthermore, these tumors do not respond well to novel agents that have been developed for ovarian cancer such as PARP inhibitors. Although there are several chemotherapy and molecular-targeted therapies available for the remaining, non-CCNE1-amplified ovarian cancers, there are currently no drugs that are effective against CCNE1-amplified tumors. In this regard, discovery of novel therapies that are specific for patients with this subtype of ovarian cancer represents an urgent unmet need and an important priority for ovarian cancer research. Our application proposes three novel strategies against CCNE1-amplified cancers, which address different aspects of CCNE1 biology. The first involves evaluation of agents that inhibit HSP90, the second involves inhibition of the interaction between RB1/FOXM1, and the third strategy involves evaluation of specific miRNAs that may be effective in combination with platinum chemotherapy or PARP inhibitors against CCNE1-amplified tumors. We propose to test these strategies in ovarian cancer cell lines with CCNE1 amplification and in patient-derived mouse models of ovarian cancer, whereby cells from patients with CCNE1 ovarian cancers have been injected and grown in mice. These models are unique because they closely resemble the primary ovarian cancer (where they came from) and therefore may offer powerful predictive information about the effectiveness of experimental drugs. We feel that this is an exciting research plan that evaluates three novel and non-overlapping strategies against CCNE1-amplified ovarian cancers, which will ultimately lead to the development of effective treatments for women with such tumors. Given that there are currently no good therapies for this chemoresistant type of ovarian cancer, it is our hope that the results of our experiments will quickly translate into significant benefit for these patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510564
Entities
People
- Panagiotis A Konstantinopoulos
Organizations
- Dana–Farber Cancer Institute
- United States Army