Precision AqT-Warhead to Treat Breast Cancer
Abstract
Breast cancer is the most common cancer in women worldwide. Statistically, roughly 1 in 8 American women will develop invasive breast cancer and approximately 40,000 women will die from breast cancer. The majority of breast cancer death is associated with metastatic disease. The object of this application is to address two of the overarching challenges of the Breast Cancer Research Program: (1) eliminate the mortality associated with metastatic breast cancer and (2) revolutionize treatment regimens by replacing drugs that have life-threatening toxicities with ones that are safe and effective. The current treatment option for metastatic breast cancer is systemic administration of cytotoxic chemotherapy drugs to extend patient life. Treatment with non-specific chemotherapy drugs usually comes with certain side effects and greatly affects a patient s lifestyle. The new trend is targeted therapy, such as the use of antibodies or small molecules that target specific proteins or signal transduction pathways. Over the years, we have learned that many of these targeted therapies eventually lead to resistance. Clinical data have shown that combination therapy with two or three drugs is effective at circumventing drug resistance acquired with monotherapy. However, combination therapy usually comes with added toxicities. Doctors have to be very careful when choosing this type of treatment for a patient. Frequent dose interruption and reductions may be required. This application aims to develop a highly efficient target-specific drug delivery system for combinational drugs using a proprietary AqueaTether[TM] (AqT[TM]) molecule as a carrier. A hyper-branched AqT[TM] molecule will be designed with multiple strategically spaced crosslinking groups at various layers. Chemotherapy drugs will be loaded onto the AqT[TM] molecule via a releasable bond. AqT[TM] molecules armed with two or more types of drugs with complementary cell killing mechanisms (called AqT[TM]-warhead) will then be linked to an antibody for target-specific delivery (called precision AqT[TM]-warhead). As all the drugs are delivered specifically to a cancer cell within a single molecule setting and the drugs are released within the cancer cell, minimum side effects and maximum effectiveness can be expected. Initially, we will test this architecture in HER2-positive breast cancer patient. HER2 is overexpressed in 20% to 25% of human breast cancers and is predictive of poor clinical outcomes. In Level I, methods will be developed (a) to synthesize hyper-branched AqT[TM] molecules, (b) for loading different drugs onto AqT[TM] molecules, and (c) for linking AqT[TM]-warhead with antibody (precision AqT[TM]-warhead). In addition, (d) the stability and release profiles of precision-AqT[TM]-warheads will be tested in vitro and (e) some initial in vitro and in vivo studies will be carried out to evaluate the toxicity, efficacy, and pharmacokinetics. This proof-of-concept work will take one and a half years to complete. Once the concept proves useful, precision-AqT[TM]-warhead will be developed into a safe and effective alternative drug for treating HER2-positive metastatic breast cancer patients. In addition, more research will be carried out to link the AqT[TM]-warhead with other types of antibodies that target proteins overexpressed on HER2-negative breast cancer cells. Precision AqT[TM]-warheads with various targeting antibodies attached will be combined to target heterogeneous cancer cells and eventually eliminate the mortality associated with metastatic breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510075
Entities
People
- Yumei Huang
Organizations
- United States Army