Mechanisms of ATF2 in Survival of Head and Neck Cancer

ATF2 在头颈癌生存中的机制

• 批准号: 6954200
• 负责人: Dianne Duffey
• 金额: $ 13.5万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-28 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6954200
• 关键词: SCID mouse; biotechnology; cell cycle; chemoprevention; cytokine; cytotoxicity; enzyme linked immunosorbent assay; flow cytometry; gel mobility shift assay; gene expression; gene targeting; gene therapy; genetic transcription; head /neck neoplasm; immunocytochemistry; neoplasm /cancer therapy; nuclear factor kappa beta; nuclear proteins; polymerase chain reaction; protein biosynthesis; squamous cell carcinoma; terminal nick end labeling; tissue /cell culture; transcription factor; tumor necrosis factor alpha; western blottings

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.

描述（由申请人提供）：这个全面的计划，以发展在口腔，咽和头颈癌（HNSCC）的治疗研究生涯的重点是假设驱动的癌症基因治疗研究。该候选人的长期目标是根据对为这些肿瘤提供生存优势的分子机制的理解，开发用于HNSCC治疗和化学预防的创新方案。通过监督实验和高级研讨会获得技术专业知识的直接目标将在提供从台式到床边的癌症基因治疗研究的完整执行的设施中实现。候选人将通过这个指导奖充分发展新的研究技能和必要的知识，成功地作为一个独立的研究人员在癌症基因治疗领域。 HNSCC是世界上第六大最常见的癌症。有效的分子治疗的发展是可取的，以尽量减少与目前的常规治疗相关的言语，吞咽和美容畸形。初步研究表明，ATF 2在HNSCC中的存活和细胞因子产生中具有明确的作用。使用转录因子ATF 2作为HNSCC的靶点，该研究将解决以下问题 具体目标： (1)证明ATF 2以组成型方式表达并具有转录活性，并且也可以通过各种处理诱导。这一目标将确定的性质和模式的ATF 2的表达和功能，因为它涉及到其他转录因子亚基。 (2)证明ATF 2功能和AP-1活性降低导致以下表型变化：a）细胞因子产生减少，B）TNF-α介导的细胞毒性，c）细胞凋亡抑制剂产生减少，d）细胞周期进程改变 (3)显示通过瘤内基因治疗递送的ATF 2显性阴性安全有效地损害HNSCC存活; TNF-α增强ATF 2的功效 本研究中的实验将证明，靶向ATF 2的肿瘤局部分子治疗可以增强HNSCC对治疗的敏感性，并减少有利于侵袭和转移的条件。这些研究将证明使用基因治疗靶向ATF 2的临床潜力。 针对该机制在人体中的治疗效果将是该研究者未来研究的目标。