Leveraging Cholesterol Homeostasis for the Prevention and Treatment of Metastatic Breast Cancer
Abstract
Problem: Despite increased survivorship among patients, breast cancer remains the second leading cause of cancer death in women. Recurrence with metastatic disease is by far the leading cause of breast cancer mortality, not the primary tumor itself. The only current therapies available for this stage of disease are very toxic, have significant side effects, and in most cases are not very effective. Being diagnosed with recurrent disease is a significant worry for survivors. Therefore, studies that may result in new targeted therapies or approaches to either prevent or treat metastatic breast cancer are urgently needed. Using mouse models, the Nelson lab has found that cholesterol and its metabolites promote metastatic disease. Furthermore, various proteins involved in the regulation of cholesterol appear to promote the immune system’s response against cancer. These findings are supported by studies indicating that patients with high cholesterol levels are more likely to develop metastatic disease, while patients taking cholesterol lowering drugs are protected. The goal of this proposal is to determine how cholesterol biology influences the immune system, thereby uncovering new strategies to treat metastasis. Vision: We will focus on two major aspects of metastatic disease where a better understanding of the basic mechanisms will likely lead to clinical breakthroughs. (1) Prevention: Emerging evidence suggests that the majority of breast cancer survivors continue to harbor cancer cells that remain in a non-proliferative or dormant state. Although it is not clear how or why, at some point these dormant cells start proliferating again, resulting in metastatic lesions. In order to come up with strategies to prevent recurrence, we need to understand what drives the reemergence of these cells. The power of prevention is well known, and exemplified by the adoption of refrigeration for the prevention of gastrointestinal cancers, anti-smoking campaigns for the prevention of lung cancer, and the recent HPV vaccine for the prevention of cervical cancers. Breast cancer survivors want strategies that they can enact on in their own lives, in order to prevent recurrence. Therefore, a large part of our proposed work will be devoted to determining how cholesterol, food preparation techniques, cholesterol breakdown products, and the cellular machinery involved in the regulation of cholesterol, may play a role in dormancy. (2) Treatment: To date, there are very limited options to treat recurrent metastatic disease, with the use of cytotoxic chemotherapy being front-line. These therapies are associated with significant side effects and leave much to be desired in terms of extending survival and quality of life. New therapies that work to turn on the immune system can be very effective, especially in melanoma. However, most breast cancer patients do not respond to these therapies. It is likely that the immune system can still play a significant role, but other factors are keeping it suppressed. Our data suggests that one such factor is cholesterol and proteins involved in its regulation. The second major focus of this proposal will be to elucidate how cholesterol biology impairs the immune system, and then utilize this information to develop novel drugs to re-train the immune system into attacking cancer. Understanding how to re-initiate the immune system would have enormous clinical potential. Approach: The Nelson lab has found that cholesterol and its regulation impact dormancy and metastatic disease and has also found that different food preparation techniques can result in differential effects on metastasis. However, it is not clear how these effects are exerted. Therefore, with the goal of revealing new dietary and therapeutic targets, in this proposal we will explore (1) the impact of cholesterol metabolism and proteins involved in its homeostatic regulation on the reemergence from dormancy and established metastatic disease and (2
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110177
Entities
People
- Erik R Nelson
Organizations
- United States Army
- University of Illinois Urbana–Champaign