Adenovirus Limitations and Tumor Targeted Gene Therapy

描述(申请人提供)：口腔和头颈部鳞状细胞癌(HNSCC)是一种毁灭性的疾病，在过去的20年里，手术、放射和/或化疗并没有提高50%的总5年生存率。为了提高存活率和降低发病率，口腔癌的治疗策略正在开发中。尽管许多肿瘤类型的临床前数据令人鼓舞，但腺病毒基因治疗的初步临床研究一直令人失望。我们假设，即使在相同组织学的头颈癌之间也存在细胞差异，从而限制了已消失的治疗反应。我们进一步认为，共享的柯萨奇和腺病毒受体(CAR)和整合素受体的变异在转导效率中起着重要作用，并转化为对腺病毒基因治疗策略的多肿瘤反应的显着差异。我们将通过解决以下特定目标来检验五个假设：1)确定新鲜的人HNSCC样本和衍生细胞系上CAR、整合素和FGF2受体的浓度；2)建立CAR或整合素的表达和Ad-tk抗肿瘤效应之间的相关性，并在体外开发绕过这些限制的FGF2重定向策略；3)使用标准腺病毒和FGF2-R重定向载体来定量研究11个NSCC系建立的肿瘤中的基因表达和对Ad-tk的治疗反应。4)采用规避治疗策略优化直接瘤内注射治疗，并引入全身性FGF2重定向治疗。我们重点研究了一种新型的成纤维细胞生长因子结合腺病毒载体。规避策略，将提高GONE转移效率和相应的治疗反应。这种新的基于成纤维细胞生长因子-2受体的重定向策略也可以安全有效地系统地递送肿瘤靶向腺病毒载体。5项对腺病毒受体和整合素在肿瘤细胞上表达作用的研究将提供一个重要的治疗信息平台，将导致更有效和更适用的临床前动物研究和人类临床研究。在登记进入临床试验之前，腺病毒受体或整合素检测可能提供一种选择、分层或评估头颈癌患者预后的手段。这一信息平台也将证明对那些希望通过开发和使用替代策略(如成纤维细胞生长因子重定向腺病毒)来规避限制的研究人员来说是有价值的。

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.