≫Combination of E1a Gene Therapy and Egfr Tyrosine Kinase Inhibitors in Tnbc: Preclinical Studies May Light up the New Therapeutic Strategy

Triple-negative breast cancer (TNBC) is characterized by the absence of the estrogen receptor alpha (ER), of the progesterone receptor (PR), and lower expression of the human epidermal growth factor receptor-2 (HER2/neu), account for approximately 15-20% of breast cancers. TNBC is associated with poor prognosis and highly metastatic phenotype due to the lack of targets treatments. Currently, some studies have shown that epidermal growth factor receptor (EGFR) is frequently overexpressed in TNBC and is considered to be an important therapeutic target. However, some patients poor response to EGFR tyrosine kinase inhibitors (EGFR-TKIs) after treatment. Therefore, the development of new drugs or combined with other treatment is very important. The adenovirus type 5 E1A (E1A) gene therapies have been tested in human breast, ovarian, and head and neck tumors clinical trials. Recent studies have shown that E1A is associated with anticancer activities by promoting the sensitivity of tumors cells to anticancer drugs. Our goal is to investigate whether and how E1A enhances EGFR-TKIs sensitization of TNBC. The specific aims as following will help us to reveal the goal. SPECIFIC AIM 1: To define the impact of E1A on EGFR-TKIs treatment of TNBC cells. 1.1 To select EGFR-TKIs-resistant TNBC cell lines. 1.2 To establish E1A-overexpressed TNBC cell lines. 1.3 To test the effects of E1A on EGFR TKIs sensitization in TNBC. SPECIFIC AIM 2: To investigate the candidate molecules involve in E1A-mediated EGFR-TKIs sensitization. 2.1 To identify the differentially expressed candidate molecules related to E1A-mediated EGFR TKIs sensitization by Human Phospho-Receptor Tyrosine Kinase Array and Micro-Western Array. 2.2 To verify whether the candidate molecules involve in EGFR TKIs sensitization. SPECIFIC AIM 3: To reveal the mechanisms responsible for regulation of candidate molecules. 3.1 To study the regulatory mechanisms involove in regulation of candidate molecules. 3-2 To further confirm the linkage between candidate molecules and subsequent biological functions and the signal transduction mediator in E1A-mediated EGFR TKIs sensitization. SPECIFIC AIM 4: To study the physiological significance of candidate molecules in vivo. 4-1. To investigate the physiological significance of candidate molecules in animal model. 4-2. To examine the clinical significance of candidate molecules in TNBC patients. The purpose of this project is to identify the biological function and possible molecular mechanisms of E1A on EGFR-TKIs sensitization in TNBC. Achievements of these specific aims will help us to understand better about functions and molecular mechanism of E1A in TNBC. Furthermore, the findings from this project may provide novel therapeutic targets or strategies in developing anti-TNBC pharmaceuticals.