ATAD3A as a Novel Target in Head and Neck Cancer

ATAD3A 作为头颈癌的新靶点

• 批准号: 9817327
• 负责人: Yong Teng
• 金额: $ 37.06万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-16 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9817327
• 关键词: ATP phosphohydrolase; Address; Biological; Clinical; Complex; Data; Development; Disease; Distant; Enzymes; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Failure; Family; Goals; Growth; Head and Neck Cancer; Head and Neck Neoplasms; Head and Neck Squamous Cell Carcinoma; Heat-Shock Proteins 90; In Vitro; Individual; MAPK3 gene; Maintenance; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Medical; Mission; Mitochondria; Molecular; Oncogenic; Oncoproteins; Outcome; Pathway interactions; Patients; Proteins; Receptor Protein-Tyrosine Kinases; Regimen; Regulation; Research; Role; Scientist; Signal Pathway; Signal Transduction; Signaling Molecule; Small Interfering RNA; Testing; Therapeutic; Therapeutic Effect; Toxic effect; Translating; Treatment Efficacy; United States National Institutes of Health; anti-cancer; base; cancer therapy; clinically relevant; clinically significant; design; effective therapy; human disease; improved; in vivo; insight; interest; nanoparticle; nanoparticle delivery; novel; novel therapeutic intervention; oncology; outcome forecast; overexpression; pre-clinical; protein complex; response; targeted treatment; therapeutic target; tumor; tumor growth; tumor progression

PROJECT SUMMARY Head and neck squamous cell carcinoma (HNSCC) remains a challenging clinical problem because of the persisting high rate of local and distant failure. Targeting epidermal growth factor receptor (EGFR) is a rational strategy given that more than 90% of HNSCC overexpress EGFR which is associated with poor prognosis. However, the clinical benefit is dampened significantly in HNSCC patients as EGFR-targeted therapy cannot suppress EGFR-independent mitochondrial oncogenic signaling, which emphasizes the need for further insights into novel comprehensive and efficacious treatment of HNSCC. We now have data demonstrating that the ATPase family AAA-domain containing protein 3A (ATAD3A), a mitochondria-localized enzyme, is required and sufficient to favor head and neck tumor growth and progression by upregulating EGFR-independent mitochondrial oncogenic signaling. These novel observations and findings raise the possibility to develop novel combination regimens by co-targeting ATAD3A and EGFR in order to eventually increase cure rate in HNSCC. The central hypothesis of this proposal is that ATAD3A forms oncogenic signaling molecules with PKCε and ERK1/2 at the mitochondria to promote head and neck tumor growth and progression, and dual inhibition of ATAD3A and EGFR represents a promising strategy to enhance anti-HNSCC treatment. The strengths of our studies should interest a range of cancer scientists and clinicians, who seek to understand the biological consequences of cancer treatment and to assess the feasibility of manipulating mitochondrial signaling pathways for therapeutic purposes. The hypothesis will be tested in the following Specific Aims. Aim 1 is to explore functional regulation and role of the mitochondrial PKCε-ATAD3A complex in HNSCC cells. Aim 2 is to illustrate the mechanism underlying ATAD3A-dependent mitochondrial ERK1/2 activation in HNSCC cells. Aim 3 is to develop new therapeutic approaches to control HNSCC progression by co-inhibiting ATAD3A and EGFR. Our overarching goal is to improve EGFR-targeted therapeutic efficacy in HNSCC by simultaneously suppressing ATAD3A-mediated mitochondrial signaling, with tumor-targeting multifunctional nanoparticles for the co-delivery of erlotinib/siRNA (anti-ATAD3A). Results from this project will significantly impact upon the design and execution of novel combination regimens for EGFR-positive HNSCC.

项目摘要 头颈部鳞状细胞癌（HNSCC）仍然是一个挑战临床问题 由于局部和不变故障的持续率持续存在。靶向表皮生长因子 鉴于超过90％的HNSCC过表达EGFR，受体（EGFR）是一种合理的策略 这与预后不良有关。但是，临床益处被显着抑制 在HNSCC患者中，作为EGFR靶向疗法不能抑制EGFR独立的 线粒体致癌信号传导，强调需要进一步了解新颖 HNSCC的全面有效治疗。我们现在有数据表明 ATPase家族AAA域含有蛋白3a（ATAD3A），一种线粒体 - 局部化酶， 需要并且足以通过上调来支持头颈肿瘤的生长和进展 EGFR非依赖性线粒体致癌信号传导。这些新颖的观察和发现 通过共同靶向ATAD3A和EGFR来提高开发新型组合方案的可能性 为了最终提高HNSCC的治疗率。该提议的核心假设是 ATAD3A在线粒体上与PKCε和ERK1/2形成致癌信号分子 促进头颈肿瘤的生长和进展，以及对ATAD3A的双重抑制 EGFR代表了增强抗HNSCC治疗的承诺策略。优势 我们的研究应该让一系列癌症科学家和临床医生感兴趣，他们试图了解 癌症治疗的生物学后果并评估操纵的可行性 用于治疗目的的线粒体信号通路。该假设将在 遵循特定目标。目标1是探索线粒体的功能调节和作用 HNSCC细胞中的PKCε-ATAD3A复合物。目标2是说明基本机制 HNSCC细胞中的ATAD3A依赖性线粒体ERK1/2激活。目标3是开发新的 通过共同抑制ATAD3A和EGFR来控制HNSCC进展的治疗方法。 我们的总体目标是通过 类似地抑制ATAD3A介导的线粒体信号传导，并具有靶向肿瘤的靶向 用于erlotinib/siRNA（抗ATAD3A）共递送的多功能纳米颗粒。结果 该项目将对新型组合的设计和执行产生重大影响 EGFR阳性HNSCC的方案。