Developing Novel Strategies for Immunoprevention of Estrogen Receptor-Negative Breast Cancer
Abstract
This proposal addresses the Overarching Challenge of Prevent breast cancer (primary prevention). Despite recent breakthroughs in breast cancer treatment (e.g., targeted therapies, immunotherapies), too many women still die of breast cancer. Ultimately, the most effective way to reduce breast cancer mortality is to prevent breast cancer. Although Tamoxifen (Tam) and selective estrogen receptor modulators (SERMs, e.g., raloxifene) have led to an approximately 50% reduction in estrogen-sensitive breast cancer in high-risk women, not all women benefit from Tam and SERMs. Currently, there is no effective way to prevent estrogen receptor negative (ER-) breast cancers. Our goal is to develop safe and effective strategies to prevent ER- breast cancer using previously untested, novel methods of immunoprevention. Our immune system is critical for preventing cancer, since our immune system, when fully functioning, has the ability to detect and destroy emerging cancer cells in our body, thereby serving as a primary defense against cancer. In this proposal, we design and test new ways to invigorate the immune system for preventing ER- breast cancer. Recently, cancer immunotherapy has demonstrated remarkable efficacy against multiple cancer types, including a fraction of ER- breast cancers. Dr. J. Allison and Dr. T. Honjo were awarded the 2018 Nobel Prize in Physiology or Medicine for their innovative research in this field. However, most agents applied in cancer immunotherapies exhibited severe and even dangerous adverse side effects, raising concerns of their applicability in immunoprevention. In addition, it is hard for T-lymphocytes, the critical immune cells that attack and eliminate cancer cells, to recognize breast cancer cells. So, it is generally difficult to induce a strong immune response against breast cancer. Consequently, breast cancer has a low response rate to current immunotherapy agents. Dendritic cells (DCs) are a small group of immune cells, which teach T-lymphocytes how to recognize invading pathogens or cancer cells. DCs play a pivotal role for the generation of effective anti-tumor immune responses. In this proposal, we will explore safe and effective ways to enhance DC function, thus reinforce T-lymphocytes’ detection and killing of early-stage breast cancer to successfully prevent ER- breast cancer development. We recently made an unexpected and exciting finding that cancer patients who took vitamin E (VitE) during immunotherapies had the lowest death rate compared to patients who took other dietary supplements during immunotherapy treatment. Additionally, among various dietary supplements we tested, VitE most powerfully boosted DC-mediated immunity. Our further study showed that VitE can improve the abilities of DCs to teach T-lymphocytes and enhance their ability to recognize cancer cells and kill cancer cells, consequently. The safety and good tolerance of VitE administration in healthy women has been demonstrated by multiple studies. Here, we propose to test whether VitE administration in combination with an ER- breast cancer vaccine (GVAX) will reinforce anti-tumor immunity and more effectively prevent ER- breast cancer onset in mouse models that develop ER- mammary tumors (Aim 1) and determine the mechanisms of how VitE enhance anti-tumor immunity (Aim 2). Our findings could be readily translated into the clinic as a novel strategy for immunoprevention of breast cancer, especially, HER2-overexpressing ER- breast cancer and basal-like ER- breast cancer. Our team has rich experience in basic and translational breast cancer research. Most importantly, our Advocate, Ms. Dorothy Paterson, has significant scientific training and has a personal interest in breast cancer prevention. She has worked with the Principal Investigator (PI), Dr. Yu, for more than 12 years to develop breast cancer prevention strategies, which form the basis of this grant application. The PI’s mother had breast ca
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210060
Entities
People
- Dihua Yu
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army