Prevention and Treatment of Breast Cancer and Its Metastasis by Targeting Macrophage Migration Inhibitory Factor (MIF)
Abstract
Breast cancer is the leading cause of mortality in a woman, accounting 23% of all cancer deaths, and one in eight women will develop invasive breast cancer over the course of their life. Currently, limited options are available for preventing development of breast cancer in high-risk individuals. Tamoxifen can be used in certain high-risk women for breast cancer prevention, but this treatment is associated with significant side effects. Different drugs are available for the treatment of breast cancer, but most of them become ineffective due to development of resistance. In addition, certain types of breast cancers, including high-grade metastatic and triple-negative breast cancer (TNBC), have limited therapeutic options available. These aggressive types of breast cancers have poor prognosis due to early metastasis to the lungs or brain and a lack of effective, established targeted therapies. Therefore, there is an utmost need to develop novel drugs for chemoprevention and/or the treatment of breast cancer. The Overarching Challenges of this project are to: identify what drives breast cancer growth; determine how to stop it; and prevent breast cancer (primary prevention). In this proposal, we are developing novel therapies for chemoprevention and/or treatment of aggressive breast cancers, which have poor prognosis due to early metastasis. Our body produces a factor named macrophage migration inhibitory factor (MIF). We and others have found that MIF is produced in high levels by women with aggressive breast cancer. Furthermore, we have also found that high levels of MIF correlate with poor prognosis. Conversely, using animal models of breast cancer, we have found that the absence of MIF significantly inhibits tumor development. MIF has been shown to inhibit immune responses that protect against breast cancer, as well as promote several other pathways that directly promote the growth of the cancer cells. However, not much is known about the mechanisms by which MIF promotes tumor growth and/or metastasis. We hypothesize that MIF is a critical factor involved in the pathogenesis of breast cancer and as such could be a target for chemoprevention and/or inhibition of tumor growth and metastasis. In this project, we propose to determine the role of MIF in breast cancer development and progression and determine whether MIF is a viable drug target for chemoprevention and/or the treatment of breast cancer and its metastasis. We will also determine how MIF modulates the tumor microenvironment and promotes cancer development, progression, and metastasis. In addition, we will determine whether MIF is a potential target for chemoprevention and/or inhibition of tumor growth and/or metastasis using complementary preclinical models including TNBC, and two novel oral MIF inhibitors, L2-4000 and CPSI-1306, developed by our industry partners for clinical use. Both these compounds have favorable drug safety profiles and have been found to be effective in the treatment of a variety of MIF-mediated diseases in experimental models. We believe that L2-4000 and CPSI-1306 have the potential to be effective chemotherapeutic, as well as anticancer therapies, and could result in a quick transition from the lab to viable drug therapies for breast cancer patients. This is especially imperative when considering the limited therapeutic options available for TNBC patients. Since metastasis is the primary contributor to the mortality rate of breast cancer, developing novel therapies against metastasis will have a huge impact on treating and preventing breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1610037
Entities
People
- Ramesh K. Ganju
Organizations
- Ohio State University
- United States Army