Defining the Effects of JAK/STAT Inhibition on the Tumor Microenvironment
Abstract
Breast cancer remains the second leading cause of cancer-related deaths in women in the United States. The development of targeted therapies has been instrumental in enhancing patient survival, specifically for patients with estrogen receptor positive (ER+) and HER2 positive (HER2+) breast cancers. Significant efforts are currently underway to develop additional targeted therapies for patients with triple-negative breast cancer and for patients with ER+ and HER2+ tumors that demonstrate resistance to endocrine therapies and trastuzumab, respectively. However, these studies have proven to be challenging for many potential reasons. It has been well established that upon treatment with targeted therapies, tumor cells acquire additional genetic mutations, leading to resistance. Tumor cells also induce additional growth promoting pathways that circumvent the effects of the targeted inhibitor. As described in this proposal, we offer an additional possible explanation that may contribute to therapeutic resistance in which at the same time that targeted therapies kill cancer cells, but they act on nearby non-tumor cells to create a tumor promoting "tumor microenvironment." The tumor microenvironment is essentially the soil in which the tumor grows and consists of non-tumor cells, matrix proteins, and blood vessels that surround the tumor. Understanding how this tumor microenvironment contributes to tumor progression is a major focus of current cancer research, and these studies address the overarching challenge to identify what drives breast cancer growth and determine how to stop it. While targeted therapies are examined extensively in preclinical studies for their effects on the tumor cells, little is known about the potential effects of these therapies on non-tumor cells that reside within tumor microenvironment. One of the prominent cell types within the microenvironment is the macrophage, which is normally involved in the immune response to fight infections. Macrophages are found in most solid tumors, including breast cancer, and it is known that macrophages are capable of contributing to tumor growth and progression. During the course of our studies, we have found that a specific, targetable, signaling pathway that is often activated in breast cancer cells is also activated in macrophages within the microenvironment. This pathway is called the JAK/STAT pathway, and when activated in tumor cells, it promotes tumor cell migration and survival. However, this pathway is also activated in macrophages located within the tumor. Using genetic approaches, we have found that loss of the JAK/STAT pathway in macrophages creates an environment that is favorable for tumor growth. This would suggest that while treatment of a breast cancer with JAK inhibitors may enhance tumor cell killing, at the same time the inhibitor may act on macrophages to establish a pro-tumorigenic microenvironment that could theoretically lead to therapeutic resistance and/or recurrence. The drug ruxolitinib, a JAK inhibitor, is currently being tested in Phase I and II clinical trials for breast cancer; thus, it is important to determine what the effects of this inhibitor are on non-tumor cells in the microenvironment. The goal of the current studies is to test the hypothesis that targeting the JAK/STAT pathway creates a favorable tumor microenvironment, which could ultimately lead to therapeutic resistance and/or recurrence. Studies using cells in culture will be performed to determine the effects of JAK/STAT inhibition on macrophages. Further studies using mouse models will be performed to determine whether treatment with the JAK inhibitor ruxolitinib creates an environment that is favorable for tumor growth. Finally, we will examine the possibility of combining ruxolitinib with anti-inflammatory drugs that are already used clinically to enhance therapeutic efficacy. Finally, these studies are not limited to JAK/STAT signaling. Many othe
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1610034
Entities
People
- Kathryn L Schwertfeger
Organizations
- United States Army
- University of Minnesota