Epigenetic Modulation of Immune-Suppressed Mesenchymal Triple-Negative Breast Cancer
Abstract
Triple-negative breast cancer (TNBC) is one of the most aggressive types of breast cancer, with shorter survival outcomes when compared to other breast cancer types. Prognosis is especially dismal for TNBC patients with metastatic disease that has spread to other tissues, with only half of patients surviving more than 1 year. TNBC, unlike some of the other types of breast cancer, is a diverse disease and is very difficult to treat because tumors lack consistent alterations that can be targeted with drugs. Recently, therapies enhancing the immune system’s response to cancer have shown promise in treating metastatic TNBC and approved to treat patients with tumors or immune cells expressing the immune suppressive protein PD-L1. To identify effective treatments for TNBC, we previously divided the disease into four distinct classes that display unique biology and immune cell presence. One class, named the mesenchymal TNBC subtype, distinctly lacks immune cells, PD-L1 expression, and the machinery needed for immune recognition of the cancer cells, making these tumors unlikely to respond to the newly approved immune therapy. We have recently identified a potential mechanism by which mesenchymal tumors restructure their genome to selectively evade the immune system. We will use our expertise in TNBC with a team of basic, applied and clinical investigators to address the overarching challenges of revolutionizing treatment by replacing standard of care with regimens that are more effective, less toxic and increase survival, and eliminating the mortality associated with metastatic breast cancer by restoring immune function through remodeling DNA structure. The goals of the proposal are to 1) determine how mesenchymal TNBCs suppress immune recognition through remodeling their DNA structure and 2) determine whether drug treatment can restore immune recognition and increase the effectiveness of immune checkpoint therapy or chemotherapy in animal models. By improving our understanding of the immune suppression mechanisms in mesenchymal TNBCs, we can identify inhibitors that reverse immune evasion and improve patient survival when used in combination with chemotherapy and immune targeted therapy. Importantly, we can rapidly advance our findings into early-phase clinical trials in patients with mesenchymal subtype metastatic TNBC before the end of the 3-year funding program.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110765
Entities
People
- Brian D. Lehmann
Organizations
- United States Army
- Vanderbilt University