Preventing Inflammatory Breast Cancer Metastases by Interrupting Cellular Stress Signaling in Lymphatic Emboli and Circulating Tumor Cell Clusters
Abstract
Overarching Challenges Addressed: (1) Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival. (2) Eliminate the mortality associated with metastatic breast cancer. Inflammatory breast cancer (IBC), manifesting as a painful, red, swollen breast, is notable for aggressive growth, resistance to standard therapy, high mortality rate, and tendency to strike younger women. Its mammographic invisibility and “inflamed” appearance derive from the cancer cells growing not as solid masses but rather, small highly mobile tumor cell clusters. These are termed tumor emboli and block lymph vessels in the skin of the breast. The environment around IBC clusters often contain immune cells called macrophages and various molecules elaborated by them that collectively create a stress on the tumor cells called chronic inflammation, which, rather than eliminating the cancer, seemingly drives it to grow more aggressively. This chronic inflammation may be genetically determined (e.g., some people have gene variants associated with greater production of inflammatory molecules), but has also been linked in epidemiologic studies to modifiable characteristics like obesity, early age at first pregnancy, and lack of breastfeeding. We have identified a signaling pathway in IBC cells that links the chronic inflammatory stress of the tumor’s environment to their aggressive behavior. We hypothesize that IBC may be controlled or destroyed by interrupting this inflammation-responsive pathway and eliminating the cells and molecules in their environment that create the chronic inflammation. This will first require a clearer picture of the various immune cells, their secreted molecules, and components of the inflammation-responsive tumor cell signaling pathway that are associated with more rapid and invasive tumor growth. We will achieve this in the first aim using a repository of IBC patient samples that have associated detailed clinical and pathologic data. We will then test whether inhibiting the tumor cell stress/inflammation responsive pathway and/or depleting the macrophages with clinically relevant drugs will suppress IBC tumor growth using innovative preclinical in vitro and in vivo models that simulate IBC patient characteristics. At the conclusion of this project, we will be poised to initiate clinical testing of whether a combination of macrophage depletion and tumor stress-responsive pathway inhibition will eliminate mortality associated with IBC, using a less toxic treatment regimen than standard chemotherapies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010153
Entities
People
- Gayathri R Devi
Organizations
- Duke University
- United States Army