Role of the Novel Interferon Epsilon in Ovarian Cancer
Abstract
Ovarian cancer is a major killer of women worldwide; 220,000 women are diagnosed annually and over one in two women will die within 5 years of diagnosis. This is due to the late detection of this disease, due in part to a lack of understanding of what happens in the early stages of tumor cell development, how the disease progresses, and how and why it spreads to other areas of the body (metastasis). Additionally, once this disease is detected (usually at a late stage), the main treatment options are based on (i) surgical removal of the many organs in the female reproductive tract (FRT) -- the uterus, fallopian tubes and ovaries -- which does not remove cancer cells that have already metastasized and (ii) platinum-based chemotherapy, to which patients can quickly develop resistance. Our proposal addresses many of these issues: it will provide further understanding of the initiation, progression, and metastasis of ovarian cancer and will evaluate a potential novel therapeutic strategy. We are doing this based on new discoveries made by our lab into the immune system in the FRT. We discovered a new protein called interferon epsilon (IFN-epsilon), which is expressed at high levels in the FRT and is critical for the activation of local immune cells, including natural killer (NK) cells and cytotoxic T cells, both known to kill cancer cells and prevent their metastasis. Interestingly, IFN-epsilon belongs to a family of proteins called the type I IFNs. The type I IFNs are known for their strong anti-tumor properties and one of them, IFN-alpha, has been used to treat different types of cancers for decades. Initial trials with IFN-alpha in ovarian cancer yielded mixed results; however, IFN-alpha is not normally present in healthy FRT. Therefore, we hypothesize that as IFN-epsilon is normally expressed in the FRT, and is designed to act on cells in that organ, it may thus offer a better therapeutic strategy and yield better results. We propose that IFN-epsilon works in two ways to inhibit ovarian cancer development. First, it directly induces cell death in cancer cells. Second, it activates immune cells, such as the NK and cytotoxic T cells, around tumors and instructs them to kill the cancer cells. As the discoverers of this protein, we are in a unique position to fully study its role in ovarian cancer and elucidate whether we can use it as a new therapy. We have evidence that IFN-epsilon expression is lost in ovarian cancer development. We found that women with high-grade serous ovarian cancer had less of this anti-tumor protein in their fallopian tubes than healthy women. Therefore, ovarian cancer may develop due to a "shutting-off" of the "tumor-inhibiting" IFN-epsilon. Our previous studies showed that IFN-epsilon is produced when there are hormones present in the FRT. It is well known that women on hormone-based contraceptives are less likely to develop ovarian cancer; this may be because they have boosted their levels of IFN-epsilon. Additionally, after menopause, women have a significant drop in hormones levels and increased chances of getting ovarian cancer. We found that post-menopausal women have much less IFN-epsilon because of this hormonal decrease, and this could be why this group of women is more at risk of ovarian cancer development. We also want to investigate another interesting link between IFN-epsilon and ovarian cancer. A mutation in the BRCA1 protein is a strong risk factor for women to develop ovarian cancer. We have evidence that BRCA1 may control IFN-epsilon expression. Therefore, in women with a mutation in BRCA1, they may not have IFN-epsilon and thus may develop ovarian cancer. We propose novel experiments to investigate this. As outlined above, this proposal addresses the two central problems in ovarian cancer: lack of understanding of why it develops and lack of new treatment options and is thus in line with the vision of the Ovarian Cancer Research Program. This proposal is a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510106
Entities
People
- Paul Hertzog
Organizations
- United States Army