Epigenome Editing for Targeted Reactivation of Tumoral FOXP3 to Treat Breast Cancers
Abstract
Metastatic breast cancer (mBCa), also known as stage IV or advanced breast cancer, is evident when BCa has spread to other organs in the body, including the lungs, bones, liver, and/or the brain. The 5-year survival rate for women with mBCa is 27%, causing the majority of deaths from BCa. Currently, there is no cure for patients with mBCa. Recently, we found that the FOXP3 gene has dual roles in tumor cells and immune cells; and is involved in tumor metastasis and in BCa patient survival. In BCa cells, FOXP3 stops the spread of cancer, whereas in immune cells, FOXP3 is a promoter of metastasis. In our original research project, fiscal year 2016 Breakthrough Award Level 1, we demonstrated that activation of FOXP3 in BCa cells inhibits their growth and metastasis. In the proposed study, we will continue to elucidate the effects of FOXP3-mediated metastatic mechanisms as well as new targeted FOXP3 gene therapy for eliminating the mortality associated with mBCa. Our preliminary analysis of more than 500 human BCa samples revealed that the combination of FOXP3-negative tumor cells and high numbers of FOXP3-positive immune cells is associated with the worst survival and in tumor metastasis. Conversely, patients with FOXP3-positive tumor cells and low numbers of FOXP3-positive immune cells show no evidence of distant metastases and no cancer-related deaths. However, the underlying mechanism remains poorly understood. Here, we hypothesize that FOXP3 is a key regulator in tumor-immune interactions for tumor metastasis and that targeting reactivation of FOXP3 in BCa cells can inhibit tumor metastasis. First, we will investigate, with cell models and animal models, the mechanisms of FOXP3-mediated tumor metastasis. Next, we will use newly developed tumor-specific technologies to target the FOXP3 gene for its reactivation in tumor cells and eliminate tumor metastasis. In future clinical applications, our identified mechanisms will not only help to understand how lethal mBCa originates and develops, but also provide the potential to yield new gene therapy for eliminating the mortality associated with mBCa. We will address the following challenges: identify why some breast cancers become metastatic; revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival; and eliminate the mortality associated with metastatic breast cancer. What types of patients will it help and how will it help them? Since the lack of FOXP3 is associated with a higher propensity for triple-negative BCa (TNBC), we will focus on TNBC. Our identified mechanism will help TNBC patients with early diagnosis, prediction of tumor metastasis, and recurrence after surgery. If metastasis and recurrence are predicted after surgery, appropriate adjuvant treatment (e.g., chemotherapy and immunotherapy) will reduce patient deaths from metastasis and recurrence. On the other hand, patients with negative biomarkers can forego any unnecessary adjuvant treatment, and overtreatment can be prevented. Also, our developed FOXP3 gene therapy has potential to prevent or eliminate tumor metastasis for BCa patients with a high risk of developing metastases. What are the potential clinical applications, benefits, and risks? Our identified mechanism will assist clinicians in early detection of aggressive BCa (with FOXP3 defect), in early prediction of tumor recurrence, and will benefit patients for appropriate selection of adjuvant treatments after surgery. If a low risk of metastasis and recurrence is predicted, patients will not need any adjuvant therapy and will avoid overtreatment. Also, our FOXP3 gene therapy will benefit BCa patients by reducing metastasis. We will develop a tumor-specific targeted gene therapy, leading to limited side effects. What is the projected time it may take to achieve a patient-related outcome? It will likely take 2 to 3 years for clinical application of our develope
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310696
Entities
People
- Lizhong Wang
Organizations
- United States Army
- University of Alabama at Birmingham