The ultimate objective of this project is to determine the ability of locally delivered docetaxel to enhance Ad-p53 antitumor activity in head and neck squamous cell carcinoma (HNSCC). Docetaxel and Ad-p53 will be delivered intratumorally and into surgical wounds. In this proposal we plan preclinical in vivo experiments in order to develop clinical trials using this approach. This is a high risk and high impact project that uses a novel approach to aggressively treat local-regional disease. In advanced HNSCC, the five-year survival rate is less than 40 percent. Since patients with advanced HNSCC have a high rate of local-regional failure (40-60 percent) with existing treatment modalities, aggressive local therapy approaches need to be developed. A higher intratumoral concentration produces a greater cytotoxic effect since tumor cell death is proportional to drug concentration. Intratumoral (IT) chemotherapy focuses high drug concentrations in solid tumors and limits total body exposure to the cytotoxic agent resulting in increased dose-related tumor cell killing and reduced toxicity. Our previous in vitro data show that docetaxel enhances Ad-p53 apoptosis in HNSCC cells in part by increasing viral transduction via upregulation of the coxsackie-adenovirus receptor. We have significant experience with gene therapy since we were investigators in the Ad-p53 Phase II trial along with the Phase I and II E1A-liposome gene therapy trials and are now participating in two Phase III and a Phase II perioperative trial (SWOG: S0011, PI: G. Yoo) using intra-wound (IW) injections of Ad-p53. Before we begin clinical trials using intratumoral (IT) and intra-wound injections (IW) of docetaxel and Ad-p53, we propose in vivo preclinical experiments to test this treatment approach. Using human HNSCC cell lines and a mouse xenograft model, we will establish the optimum dose and the activity of IT docetaxel when combined with IT Ad-p53. Furthermore, we will monitor alterations in expression of key biomarkers. Since we also want to develop delivery of docetaxel + Ad-p53 by perioperative injections, we will determine the tumor growth in a microscopic residual model and surgical wound healing toxicity using IW docetaxel and Ad-p53. Favorable data from the proposed project will lead to the development of clinical trials using intratumoral and intra-wound injections of docetaxel and Ad-p53.
| Yoo, George H; Subramanian, Geetha; Ezzat, Waleed H et al. (2010) Intratumoral delivery of docetaxel enhances antitumor activity of Ad-p53 in murine head and neck cancer xenograft model. Am J Otolaryngol 31:78-83 |
| Yoo, George H; Tran, Vivian R; Lemonnier, Lori A et al. (2007) BMS-275183-induced gene expression patterns in head and neck carcinoma. Am J Otolaryngol 28:309-15 |
| Yoo, George H; Subramanian, Geetha; Boinpally, Ramesh R et al. (2005) An in vivo evaluation of docetaxel delivered intratumorally in head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 131:418-29 |
| Yoo, George H; Lin, Ho-Sheng; Iskander, Andrew J et al. (2005) Docetaxel associated pathways in cisplatin resistant head and neck squamous cell carcinoma: a pilot study. Laryngoscope 115:1938-46 |
| Yoo, George H; Piechocki, Marie P; Oliver, Jeffery et al. (2004) Enhancement of Ad-p53 therapy with docetaxel in head and neck cancer. Laryngoscope 114:1871-9 |
| Shibuya, Terry Y; Kim, Sanghun; Nguyen, Kevin et al. (2004) Bioactive suture: a novel immunotherapy for head and neck cancer. Clin Cancer Res 10:7088-99 |
