Mechanisms of ATF2 in Survival of Head and Neck Cancer

ATF2 在头颈癌生存中的机制

• 批准号: 7262581
• 负责人: Dianne Duffey
• 金额: $ 13.5万
• 依托单位: YALE UNIVERSITY
• 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 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7262581
• 关键词: ATF2 gene; Address; Apoptosis; Apoptosis Inhibitor; Area; Award; Binding; Binding Sites; Cell Cycle; Cell Cycle Progression; Cell Survival; Chemoprevention; Clinical; Condition; Cytotoxic agent; Data; Deformity; Deglutition; Development; Dominant-Negative Mutation; Dose; Educational workshop; End Point; Endopeptidases; Event; Future; Genetic Transcription; Goals; Growth; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Histology; Human; In Vitro; Knowledge; Localized; Malignant Neoplasms; Mediating; Mentors; Modeling; Molecular; Nature; Neoplasm Metastasis; Oncogenes; Oropharyngeal; Pattern; Peptide Hydrolases; Peptides; Play; Predisposition; Production; Proteins; Recombinants; Research; Research Personnel; Resistance; Role; Speech; Technical Expertise; Testing; Therapeutic Studies; Toxic effect; Transcription Factor AP-1; Transcriptional Activation; Treatment Efficacy; Treatment Protocols; Tumor Necrosis Factor-Beta; Tumor Necrosis Factor-alpha; base; career; concept; cytokine; cytotoxicity; gene therapy; human TNF protein; improved; in vivo; innovation; neoplastic cell; research study; response; size; skills; survivin; transcription factor; transgene expression; treatment effect; tumor

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 understanding of the 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-a 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-slpha inhances the efficacy of ATF2 dominant negative treatment. 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.

该综合计划旨在发展口腔癌、咽癌和头颈癌治疗领域的研究事业 （HNSCC）专注于假设驱动的癌症基因治疗研究。候选人的长期目标是发展 基于对分子机制的了解，治疗和化学预防 HNSCC 的创新方案 为这些肿瘤提供生存优势的机制。通过以下方式获得技术专业知识的直接目标 监督实验和高级研讨会将在提供完整癌症治疗的设施中举行 从实验室到临床的基因治疗研究。候选人将通过这个指导奖项充分发展新的 作为癌症基因治疗领域的独立研究者取得成功所必需的研究技能和知识。 HNSCC 是世界上第六大常见癌症。开发有效的分子治疗方法是必要的 最大限度地减少与当前常规治疗相关的言语、吞咽和美容方面的畸形。 初步研究表明 ATF2 在 HNSCC 的存活和细胞因子产生中发挥着明确的作用。使用转录 将 ATF2 作为 HNSCC 的靶标，该研究将解决以下问题 具体目标： (1) 证明 ATF2 以组成型方式表达并具有转录活性，并且也可以通过以下方式诱导： 各种治疗。这一目标将确定 ATF2 表达和功能的性质和模式，因为它与 其他转录因子亚基。 (2) 证明 ATF2 功能和 AP-1 活性的降低会导致以下表型变化： 细胞因子的产生减少，b) TNF-a 介导的细胞毒性，c) 细胞凋亡抑制剂的产生减少， d) 细胞周期进程的改变 (3) 表明ATF2显性失活通过瘤内基因治疗安全有效地损害HNSCC 生存； TNF-α 增强 ATF2 显性阴性治疗的功效。 本研究中的实验将证明针对 ATF2 的肿瘤的局部分子治疗可以增强 HNSCC 对治疗的敏感性并减少有利于进展和转移的条件。这些 研究将证明使用基因疗法靶向 ATF2 的临床潜力。 针对人类这一机制的治疗效果将是该研究者未来研究的目标。

项目成果

Activating transcription factor-2 in survival mechanisms in head and neck carcinoma cells.

• DOI: 10.1002/hed.21648
• 发表时间: 2011-11
• 期刊: HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK
• 影响因子: 2.9
• 作者: Duffey, Dianne;Dolgilevich, Svetlana;Razzouk, Sleiman;Li, Lina;Green, Ross;Gorti, Goutham Krishna
• 通讯作者: Gorti, Goutham Krishna