Adenovirus Limitations and Tumor Targeted Gene Therapy

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DESCRIPTION (provided by applicant): Squamous cell carcinoma of the oral cavity and head and neck (HNSCC) is a devastating disease in which surgery, radiation and/or chemotherapy have not improved the 50 percent overall 5 year survival over the past 20 years. In an attempt to improve survival and reduce morbidity, gone therapy strategies are being developed for oral cancer. Despite encouraging preclinical data in many tumor types, initial clinical studies with adenovirus gene therapy have been disappointing. We posit that cellular differences exist even among head and neck cancers of the same histology that limit gone therapy responses. We further posit that variations in shared Coxsackie and adenovirus receptor (CAR) and integrin receptors play a major role in the transduction efficiency and translates to a significant variation in multi-tumor responses to adenovirus gene therapy strategies. We will test five hypotheses by addressing the following Specific Aims: 1) Determine the concentration of CAR, integrins, and FGF2 receptor on fresh human HNSCC samples and derived cell lines; 2) Establish the correlation between expression of CAR or integrin and Ad-tk anti-tumor effects and develop a FGF2 retargeting strategy in vitro that circumvents these limitations; 3) Quantify gene expression and therapeutic response to Ad-tk using both standard adenovirus and FGF2-R retargeted vectors in tumors established from 11NSCC lines. 4) Optimize direct linter-tumor injection therapy using circumventing treatment strategies and introduce systemic FGF2 retargeting therapy. We focus on a newly created fibroblast growth factor (FGF) conjugated adenovirus vector to develop a! Circumventing strategy that will improve gone transfer efficiency and corresponding therapeutic response. This novel FGF-2 receptor-based retargeting strategy may also allow safe and effective systemic delivery of tumor targeted adenovirus vectors. Five investigations regarding the role of adenovirus receptor and integrin expression on tumor cells will provide a platform of important gone therapy information that will lead to more effective and applicable preclinical animal studies and human clinical investigation. Adenovirus receptor or integrin testing prior to enrollment into a clinical trial may provide a means of selecting, stratifying, or assessing outcomes in head and neck cancer patients. This platform of information will also prove valuable to investigators who wish to circumvent limitations by developing and using alternative strategies such as FGF adenovirus retargeting.