A Targeted Mitochondrial Luminoptogenetic Gene Therapy to Treat Triple-Negative Breast Cancer
Abstract
Rationale: The triple-negative breast cancer (TNBC) is highly aggressive, metastatic, and recurrent. TNBC cells often develop resistance to standard cytotoxic chemotherapies, which mediates tumor cells to regrow after primary treatment and results in poor clinical benefits of chemotherapy. The major obstacles to succeed in TNBC treatment are drug resistance caused by the cancer cells’ repairing ability, antigen loss during treatment, or tumor recurrence. Therefore, novel anti-TNBC strategies that can overcome these barriers are urgently needed. Mitochondria are the powerhouse of cells and play a pivotal role in regulating cell functions. Destroying mitochondrial function using synthesized heterologous genes can bypass the repair of signaling transduction pathways, effectively kill cancer cells, and subsequently prevent the development of drug resistance, antigen loss and recurrence, leading to a promising TNBC therapy. Based on this notion, we have developed a mitochondrial-targeted luminoptogenetics technology that effectively killed TNBC cells within the short term and activated the integrated immune functions, underscoring its great potential to treat and eliminate TNBC. This project will develop a new mitochondrial-targeted gene therapy and evaluate the anti-TNBC efficacy in animal models. Objective: In our preliminary studies, we have for the first time developed a mitochondrial luminoptogenetic that causes substantial cell death and significantly reduces tumor volume in an animal study. Moreover, we have established TNBC-targeted monoclonal antibody-exosome-associated-adeno-associated virus (mAb-Exo-AAV), which not only delivers therapeutic genes but facilitates immunotherapy in tumor microenvironment. The objectives of this project are to harness the synergistic effects of AAV-facilitated mitochondrial luminoptogenetics to selectively, quickly, and completely eliminate TNBC cells in vivo. The central hypothesis is that the mAb-Exo-AAV carrying mitochondrial-targeted gene therapy can effectively treat TNBC with a limited side effect via integrated anti-cancer mechanisms (i.e., mitochondria depolarization-caused direct cancer cell death and immunotherapy-mediated clearance of residual cancer cells). Aims: Our mitochondrial gene therapy will be further developed and rigorously evaluated. We will first construct targeted AAV carrying mitochondrial luminoptogenetic genes, assess its anti-cancer efficacy in TNBC cells and xenograft mouse models, and investigate the underlying anti-TNBC mechanisms of luminoptogenetics. Then we will develop a platform of large-scale mAb-Exo-AAV biomanufacturing, evaluate the TNBC specificity, and assess the synergetic therapeutic values (i.e., direct cell death and immune function) in immunocompetent models. Significance: The challenge in TNBC therapy is to prevent tumor recurrence while minimizing adverse effects. Our synergetic mitochondrial luminoptogenetics can deliver highly cytotoxic therapeutic gene to TNBC cells and activate tumoral immunity, limit adverse effects, reduce drug resistance, enhance anti-tumor immunity, prevent recurrence and spreading, and eventually improve the quality of life and the survival of patients who suffer from TNBC. Thus, our proposed work will provide a breakthrough for new TNBC therapeutic approaches by addressing two FY20 DOD BCRP overarching challenges, “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.” Ultimate Applicability of the Research: Which overarching challenge(s) does this research address? “Revolutionize treatment regimens” and “Eliminate the mortality associated with metastatic breast cancer.” What types of patients will it help and how will it help them? This research will help to eliminate tumor recurrence and metastasis in TNBC patients. What are the potential clinical applic
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110066
Entities
People
- Xiaoguang Margaret Liu
Organizations
- United States Army
- University of Alabama at Birmingham