Deciphering and Intercepting Messages Between Cancer Cells and Cells in the Breast Cancer Microenvironment: Roles for Intracellular Calcium Signaling
Abstract
This application addresses the overarching challenge of eliminating the mortality associated with metastatic breast cancer by transforming treatment regimens and replacing them with therapies that are more effective, less toxic, and that increase survival. It is predicted that there will be 268,600 new cases of invasive breast cancer diagnosed in the USA in 2019. Unfortunately, about 12% of women in the USA will one day develop invasive breast cancer. Early detection and improved therapies have increased survival, but current therapies are ineffective for many women because they have breast cancer subtypes that reoccur and cannot be specifically targeted using the drugs that are very effective against other breast cancer subtypes (triple-negative). Although new treatments are being tested in clinical trials, it is already clear that these will be ineffective for many women with triple-negative breast cancers. Our research team members are experts in understanding how breast cancer cells communicate using calcium and how calcium channels in cancer cells are targets for drugs to treat breast cancer. Calcium channels are good targets for drug development because there are many types of calcium channels (>50) in the body and they are amenable to the design of drugs that can activate them or inhibit them. For example, drugs that act on specific calcium channels have been used for conditions such as high blood pressure and specific types of pain for decades, but only recently have calcium channels been considered as drug targets for cancers. The study we propose herein is only possible due to our advances in knowledge and methodology funded partially by the Breakthrough Award mechanism. Our work over the last decade has been critical in making the link between calcium and cancer, and we are uniquely placed to continue our work as described in this Expansion Award. Our work in the Breakthrough Award looked at calcium channels in the “tumor microenvironment,” the normal cells that surround cancer cells and are believed to contribute to the spread of breast cancer to other parts of the body (metastasis). It is now widely recognized in the research community that therapeutically targeting these microenvironment cells, not just cancer cells, may allow us to control breast cancer progression and improve treatment effectiveness. Indeed, our work showed that the way calcium enters a cell changes in one of the cell types (fibroblasts) of the tumor microenvironment, and we showed that a calcium channel inhibitor used clinically for cardiovascular disease, as well as silencing the channel using molecular biology tools, could prevent the induction of a fibroblast phenotype associated with the ability of breast cancers to spread throughout the body. These are important pieces of scientific knowledge that will help us to understand the complex environment surrounding the tumor cell and subsequently how we can disrupt this environment to treat cancer. In an independent project in our laboratory, we developed a novel technique that provides us with a window into calcium signaling events in cells that occur over hours and even days. Of most relevance to this proposal, this now allows us to study the entire period, not just a snapshot, during which a breast cancer cell undergoes cell death. Combining the results of our Breakthrough Award and our advance in technical knowledge gives us the ability to provide a quantum leap in assessing the impact of the tumor microenvironment and the intersection with calcium channels and how we can best target these channels. Because there are clinically used calcium channel drugs already on the market, there is the potential to repurpose these drugs to delay, or treat, advanced breast cancer decades faster than having to design new drugs that would need to be extensively tested for efficacy and safety before becoming available for clinical use. In summary, this research team has a unique
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010668
Entities
People
- Gregory R Monteith
Organizations
- United States Army
- University of Queensland