Overcoming the Limitations of Endocrine Therapy for Ovarian Cancer
Abstract
Ovarian cancer is a complex and heterogeneous disease that is the leading cause of death among gynecologic malignancies. Epidemiological studies have suggested that there is a link between steroid hormones and ovarian cancer risk. The steroid hormone, estrogen, has been demonstrated to play a key role in driving the progression of breast and endometrial cancers. Concordantly, anti-estrogen treatments have proven to be quite effective at treating these cancers. Estrogen receptor (ER) belongs to the family of nuclear steroid hormone receptors that act as transcription factors mediating the transcription of genes involved in cell proliferation and survival. However, the role of ER in ovarian cancer is poorly understood. The majority of high-grade serous and endometrioid ovarian tumors express ER at high levels; however, clinical trials using anti-estrogen treatments have failed to show much clinical benefit. We have generated preliminary data that suggest that ER Alpha is transcriptionally active in certain ovarian cancer cell lines, and the transcriptional program it regulates is different from what ER regulates in breast cancer. We postulated that the reason why anti-estrogen endocrine therapies are not effective in ovarian cancer is due to the existence of inherent mechanisms of resistance in ovarian cancer. We hypothesized that estrogen-activated negative feedback loops in ovarian cancer cause the limited clinical efficacy of ER-targeted endocrine therapies. We plan to utilize genome-wide CRISPR/Cas9 genetic screens to identify the genes responsible for driving negative feedback of the estrogen pathway. Additionally, this technique will also allow us to identify the key genes that are responsible for driving resistance and sensitivity to anti-estrogen treatments. We then plan to validate these genes in a panel of ovarian cancer cell lines and patient-derived xenograft models of ovarian cancer. We will then explore the essential cofactors that partner with ER Alpha to turn on the transcription of estrogen-dependent genes and pathways. Our project may provide insight into understanding the failure of endocrine therapy in ovarian cancer and may suggest new combinatorial therapies that would be more efficacious. If successful, this study may suggest a novel treatment paradigm for ovarian cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910147
Entities
People
- Myles A. Brown
Organizations
- Dana–Farber Cancer Institute
- United States Army