ATAD3A as a Novel Target in Head and Neck Cancer

项目摘要 头颈部鳞状细胞癌（HNSCC）仍然是一个具有挑战性的临床问题 因为本地和远程故障的持续高比率。靶向表皮生长因子 考虑到超过90%的HNSCC过表达EGFR，因此， 这与预后不良有关。然而，临床效益显著降低 在HNSCC患者中，EGFR靶向治疗不能抑制EGFR非依赖性 线粒体致癌信号，强调需要进一步了解新的 综合有效治疗HNSCC。我们现在有数据表明， ATP酶家族含AAA结构域的蛋白3A（ATAD 3A），一种位于线粒体的酶， 需要并且足以通过上调 EGFR非依赖性线粒体致癌信号传导。这些新的观察和发现 通过共靶向ATAD 3A和EGFR，提高开发新型联合治疗方案的可能性 以最终提高HNSCC的治愈率。这一提议的核心假设是 ATAD 3A与PKCε和ERK 1/2在线粒体上形成致癌信号分子， 促进头颈部肿瘤的生长和进展，以及ATAD 3A和 EGFR代表了增强抗HNSCC治疗的有前景的策略。的优势 我们的研究应该引起一系列癌症科学家和临床医生的兴趣，他们寻求了解 癌症治疗的生物学后果，并评估操作的可行性， 线粒体信号传导途径用于治疗目的。这一假设将在 遵循具体目标。目的1探讨线粒体的功能调控及其在细胞凋亡中的作用 HNSCC细胞中的PKCε-ATAD 3A复合物。目的2是阐明其机制 HNSCC细胞中ATAD 3A依赖性线粒体ERK 1/2活化。目标3：开发新的 通过共抑制ATAD 3A和EGFR来控制HNSCC进展的治疗方法。 我们的首要目标是通过以下方法提高EGFR靶向治疗HNSCC的疗效： 同时抑制ATAD 3A介导的线粒体信号传导， 用于共递送埃罗替尼/siRNA（抗ATAD 3A）的多功能纳米颗粒。结果 该项目将对新组合的设计和执行产生重大影响， EGFR阳性HNSCC的治疗方案。

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.