Mechanisms of ATF2 in Survival of Head and Neck Cancer

描述(由申请人提供)：这项旨在发展口腔、咽部和头颈癌(HNSCC)治疗研究生涯的综合计划，重点是假说驱动的癌症基因治疗研究。候选人的长期目标是基于对为这些肿瘤提供生存优势的分子机制的了解，开发治疗和化学预防HNSCC的创新方案。通过有监督的实验和高级研讨会获得技术专长的直接目标将在设施中实现，这些设施提供从桌面到床边的完整癌症基因治疗研究。候选人将通过这个导师奖充分发展新的研究技能和知识，以在癌症基因治疗领域成为一名成功的独立研究者。 人类非小细胞肺癌是世界上第六大常见癌症。开发有效的分子治疗方法是可取的，以最大限度地减少与当前传统治疗方法相关的言语、吞咽和美容畸形。初步研究表明，ATF2在HNSCC的生存和细胞因子产生中起着明显的作用。使用转录因子ATF2作为HNSCC的靶点，这项研究将解决以下问题 具体目标： (1)证明ATF2是以结构性方式表达和转录活性的，也可以被各种处理诱导。这一目标将决定ATF2的表达和功能的性质和模式，因为它与其他转录因子亚基相关。 (2)表明atf2功能和ap-1活性的降低导致下列表型变化：a)细胞因子的产生减少，b)肿瘤坏死因子-α介导的细胞毒性，c)凋亡抑制物的产生，d)细胞周期进程的改变。 (3)肿瘤内基因治疗的ATF2显性阴性可安全有效地降低HNSCC的存活率；肿瘤坏死因子-α可增强ATF2的疗效。 本研究中的实验将证明，以ATF2为靶点的局部分子治疗可以提高HNSCC对治疗的敏感性，减少有利于进展和转移的条件。这些研究将证明使用基因治疗靶向ATF2的临床潜力。 针对人类这一机制的治疗效果将是这位研究者未来研究的目标。

DESCRIPTION (provided by applicant): This comprehensive plan to develop a research career in the treatment of oral, pharyngeal and head and neck cancer (HNSCC) focuses on hypothesis-driven cancer gene therapy research. The candidate's long-term goal is to develop innovative regimens for the treatment and chemoprevention of HNSCC based on the understanding of molecular mechanisms that provide survival advantages to these tumors. Immediate goals of gaining technical expertise through supervised experiments and advanced workshops will be met in facilities that provide for complete execution of cancer gene therapy studies from benchtop to bedside. The candidate will fully develop through this mentored award the new research skills and knowledge necessary to succeed as an independent investigator in the area of cancer gene therapy. HNSCC is the 6th most common cancer in the world. The development of effective molecular treatment is desirable to minimize the deformities of speech, swallowing and cosmesis associated with current conventional treatments. Preliminary studies show a clear role for ATF2 in survival and cytokine production in HNSCC. Using the transcription factor ATF2 as a target in HNSCC, the study will address the following Specific Aims: (1) Demonstrate that ATF2 is expressed and transcriptionally active in a constitutive fashion and can also be induced by various treatments. This aim will determine the nature and patterns of ATF2 expression and function as it relates to other transcription factor subunits. (2) Demonstrate that reduction of ATF2 function and AP-1 activity results in the following phenotypic changes: a) decreased production of cytokines, b) TNF-alpha mediated cytotoxicity, c) decreased production of inhibitors of apoptosis, and d) alterations of cell cycle progression (3) Show that ATF2 dominant negative delivered by intratumoral gene therapy safely and effectively impairs HNSCC survival; TNF-alpha inhances the efficacy of ATF2 Experiments in this study will prove that localized, molecular treatment of tumors targeting ATF2 can enhance susceptibility of HNSCC to treatments and decrease conditions favorable for pregression and metastasis. These studies will demonstrate the clinical potential of targeting ATF2 using gene therapy. Therapeutic efficacy targeting this mechanism in humans will be the aim of future studies by this investigator.