Elucidating and Exploiting SAMHD1 for Breast Cancer Therapy
Abstract
Breast cancer is the most commonly diagnosed non-skin cancer in women and the second leading cause of cancer death in women in the United States. Despite recent advances in improving treatment outcomes, the overall impact of breast cancer remains devastating due to how common it is. Major challenges for the eradication of breast cancer include the need to conquer the problems of overtreatment and the need to revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival. This is especially important for patients with triple-negative breast cancer (TNBC) who do not respond to more tumor-specific treatments such as tamoxifen or herceptin and thus are treated with less tumor-specific treatments such as chemotherapy and radiation therapy and have poor clinical outcomes. In recent years, immune therapy has emerged as a promising treatment option for patients with breast cancer; however, only about 10% of breast cancer patients will respond. Thus, there is an urgent need to understand why many breast cancer patients do not respond so that novel approaches can be developed to improve the efficacy of immune therapy. Our lab and others have found that SAMHD1, a protein that functions as a HIV-1 restriction factor and is mutated in Aicardi Goutières syndrome (AGS), a rare autoimmune disorder, has a new role in resecting the ends of DNA double-strand breaks (DSB) or stalled DNA replication forks to prevent the accumulation of DNA in the cytoplasm of cells that activates the cGAS-STING pathway to induce an innate immune response that facilitates the recruitment and stimulation of CD8+ T cells that attack cancer cells. Significantly, SAMHD1 is overexpressed in up to 27% of breast cancers and its high expression is associated with poor outcomes in breast cancer patients, suggesting that SAMHD1 may be a promising therapeutic target for cancer therapy. We have also identified a novel immunologic niche in breast cancer consisting of stem-cell like CD8+ T cells that are essential for a robust immune response and that is associated with improved clinical outcomes. Finally, we developed a novel therapeutic strategy for targeting SAMHD1 in tumors whereby a natural viral accessory protein called Vpx, which targets SAMHD1 for degradation, is packaged in virus-like particles (VLP) and show that it can degrade SAMHD1 in tumors. We hypothesize that SAMHD1 governs the resistance of breast cancer to immune therapy at least in part through its role in suppressing the accumulation of cytosolic DNA and activation of the innate immune response that potentiates immune therapy by stimulating stem cell-like CD8+ T cells. Targeting SAMHD1 for degradation with VLPs containing Vpx sensitizes resistant breast cancer to immune therapy. We propose to determine the mechanism by which SAMHD1 directs immunologic dynamics underlying response to immune therapy in breast cancer and establish proof of concept that targeting SAMHD1 with VLPs containing Vpx sensitizes resistant breast cancer tumors to immune therapy. We will use multiple approaches, including with human breast cancer patient samples and breast cancer mouse models. Completion of this research will provide new insights into how SAMHD1 directs immunologic dynamics underlying anti-tumor immunity in breast cancer via stimulation of stem cell-like CD8+ T cells. This work will also elucidate the significance of SAMHD1 as a potential rationale-driven biomarker for selecting breast patients who may benefit from immune therapy. Finally, this work will establish proof of concept for the use of VLPs containing Vpx in targeting SAMHD1 as a novel therapeutic approach for overcoming breast cancer resistance to immune therapy that may significantly improve clinical outcomes for patients with breast cancer. Our research team, which includes two board-certified physician-scientists as Partnering Principal Investigators, is well positioned to rapidly translate knowledge gai
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310193
Entities
People
- Zachary Buchwald
Organizations
- Emory University
- United States Army