Role of Ceramide Kinase and Ceramide-1-Phosphate in Endocrine-Resistant Breast Cancer
Abstract
Approximately 75% of all breast tumors are estrogen receptor a (ER) positive. Most women with these tumors initially respond well to endocrine therapy (ET), such as tamoxifen or aromatase inhibitors. However, 30%-50% of women will experience relapse either while still on these drugs or following the standard 5 years of ET. Given that the majority of breast cancers are ER+, it is estimated that over 80,000 women with newly diagnosed breast cancer patients each year may eventually develop a recurrent ER+ tumor. When these tumors recur, they tend to retain ER expression yet are resistant to additional ET. As a result, the majority of breast cancer metastases, as well as the majority of breast cancer fatalities, each year result from ER+ disease. Clearly, new treatment regimens are needed to impact survival of women with recurrent, metastatic, ET-resistant ER+ breast cancer. The overarching challenge our work will address is how to revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival. We have identified a novel lipid pathway that becomes active in ET-resistant breast cancers and found that inhibiting this pathway specifically kills ET-resistant breast cancer cells. Importantly, it appears that by inhibiting this pathway, we alter ET-resistant cells so that they regain responsiveness to endocrine agents, such as tamoxifen. The work we propose will test (i) which types of ET-resistant breast cancers rely on this pathway and (ii) what proteins are involved in this pathway and are required for survival of ET-resistant cells. We believe that the work we propose is high-risk/high-reward and that the clinical applicability would be in identifying completely novel therapeutic targets in ET-resistant breast cancer. Drugs could be designed to target the key enzyme that we are studying or we may find other players in the pathway that are known drug targets. These drugs could potentially be repurposed to treat women with ET-resistant breast cancers. One of the major benefits that we may find from our work is that women may be able to take very low doses of drugs targeting this pathway in combination with known agents in endocrine therapy. Thus, the overall impact of our proposed work will be to advance our understanding of a novel pathway in promoting growth and survival of ET resistance. As a result, this project may produce novel therapeutic targets for treatment of ET-resistant, ER+ breast cancer, thereby having the potential to impact survival of women with this aggressive form of disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010486
Entities
People
- Jonna Frasor
Organizations
- United States Army
- University of Illinois at Chicago