Triple-negative breast cancers (TNBC) represent 10%-15% of all breast cancers and are defined by the lack of estrogen, progesterone, and HER2 receptors. Because of the lack of any specific targets, TNBCs are currently treated with toxic drugs or chemotherapy. In order to find safe and specific targets for TNBC therapy, we applied state-of-the-art and highly specialized technology to identify proteins that are in the active form and drive the cell machinery for cell growth, migration, etc. We discovered one such protein, namely AXL, which is located on the tumor cell surface and is aberrantly activated leading to cell doubling and cell migration. This was confirmed by specifically reducing the production of the AXL protein. We now propose to pursue this discovery to the further exploration of the therapeutic potential of targeting AXL in TNBC. We will use a highly specific humanized AXL-targeting antibody to develop a novel antibody drug conjugate (ADC), which can not only specifically target cancer cells with high AXL expression but also will kill the AXL high cancer cells. Instead of using breast cancer cell lines cultured in petri dish for many years, we will test the newly developed ADC using our large collection of TNBC tumors directly taken from patients and implanted in mice. This will ensure the discovery from our proposed study is highly relevant to the clinical application and lead to higher rate of success in optimizing therapeutic strategies for patients with TNBC. In addition to evaluation of the efficacy of this novel treatment, we will also develop a novel image system to non-invasively monitor drug delivery and dynamic distribution in drug-treated preclinical animal tumor models. Finally, we will also develop a mass spectrometry-based detection method to accurately measure not only the AXL protein level but also its enzymatic activity in TNBC tumors. This is critical for providing personalized therapy for patients that can benefit from this promising targeted therapy. Our proposed studies, if successful, will help (i) define AXL as a novel therapeutic target for TNBCs and (ii) provide an antibody-based personalized immunotherapy for TNBC patients with activated AXL that can potentially replace current highly cytotoxic chemotherapy. New clinical trials based on the humanized monoclonal antibody drug conjugate against AXL could be the direct result of our proposal for evaluating its efficacy in patients with TNBC. Our proposal thus has the very real potential to provide an effective therapeutic strategy to reduce mortality and thereby improving the prognosis of patients with TNBCs.
|Effective start/end date||9/1/19 → 8/31/22|
- U.S. Army: $786,814.00