Dual CD24/CD276 Targeting Therapies for Triple-Negative Breast Cancer
Abstract
Breast cancer affects about one in eight women worldwide, and targeted therapies to three common receptors (ER, PR, and HER2) on breast cancer cells have decreased the death rate by about 40% over the last 25 years. Unfortunately, these receptors are not expressed in triple-negative breast cancers (TNBC, ER-/PR-/HER2-), which affects 10% to 20% of diagnosed patients. The standard chemotherapies (e.g., doxorubicin, paclitaxel, and gemcitabine) available for patients with TNBC have poor clinical benefit, severe adverse effects, and the challenge of recurrence due to drug resistance. Recently, therapies that combine specific anti-cancer antibodies with toxic drugs have been developed. These therapies, called antibody-drug conjugates (ADCs), can deliver toxic drugs specifically to the tumor cells and not to healthy cells, maximizing antitumor effects while minimizing adverse effects. However, ADCs that eliminate TNBC cells have not yet been developed. In our preliminary studies, we first identified targetable cell surface receptors in TNBC cells (CD24 and CD276). We also developed tumor-specific antibodies and identified toxic drugs that kill TNBC cells. We then developed ADCs that bear cytotoxic drugs and target TNBCs, and we validated them for in vivo safety and in vitro anti-TNBC efficacy. Our objective-central hypothesis is that the specific targeting and killing of primary TNBC cells, achieved by administering our potent ADC-based therapy after surgery, can effectively eliminate TNBC and prevent its metastasis and recurrence. We will rigorously evaluate our ADCs to treat TNBC. For our ADCs that target CD24, we will identify the most efficient strategy by use of cell lines and mouse models. Next, we will evaluate the capacity of combined CD24/276 ADCs to eliminate TNBC and prevent tumor recurrence, and tumor spreading in mouse models. Finally, we will use preclinical animal models, including patient-derived xenograft models, to test the clinical applications of these ADCs by administering them in combination to treat metastatic cells after surgical removal of the primary TNBC tumor. A challenge in TNBC therapy is to prevent tumor recurrence while minimizing adverse effects. Our ADC combination therapy can deliver highly toxic drugs into TNBC cells, limit adverse effects, reduce drug resistance, enhance antitumor immunity, prevent recurrence and spreading, and 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 fiscal year 2022 (FY22) Depart of Defense (DOD) Breast Cancer Research Program (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. What types of patients will it help and how will it help them? This research will help to eliminate tumor recurrence and metastasis for patients with CD24+ and/or CD276+ TNBC. What are the potential clinical applications, benefits, and risks? This study will develop targeted clinical therapy (after surgery) that benefits TNBC patients with fewer toxic effects. What is the projected time it may take to achieve a patient-related outcome? When effective therapies are developed in the proposed study, we will immediately assess and validate these therapies through a clinical trial, which will take 3 to 5 years for the clinical application of our findings. What is the likely impact of this study on the BCRP s mission of ending breast cancer? Our developed therapy, which is more specific, effective, and less toxic, will prevent TNBC recurrence and metastasis, and thereby contribute to the BCRP s mission of ending breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310648
Entities
People
- Runhua Liu
Organizations
- United States Army
- University of Alabama at Birmingham