ATAD3A as a Novel Target in Head and Neck Cancer

项目总结 头颈部鳞状细胞癌(HNSCC)仍然是一个具有挑战性的临床问题 由于本地和远程故障率居高不下。靶向表皮生长因子 受体(EGFR)是一种合理的策略，因为90%以上的HNSCC过度表达EGFR 这与预后不良有关。然而，临床益处显著降低。 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，强调需要进一步洞察新的 综合有效的治疗HNSCC。我们现在有数据表明， ATPase家族AAA域包含蛋白3A(ATAD3A)是一种线粒体定位的酶， 是必要的，并且足以通过上调来促进头颈部肿瘤的生长和进展 不依赖于EGFR的线粒体致癌信号。这些新奇的观察和发现 提高通过共同靶向ATAD3A和EGFR开发新的联合方案的可能性 以最终提高HNSCC的治愈率。这项提议的中心假设是 ATAD3A与线粒体上的PKCε和ERK1/2形成致癌信号分子 促进头颈部肿瘤的生长和进展，并双重抑制ATAD3A和ATAD3A EGFR是一种有前景的加强抗HNSCC治疗的策略。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，他们试图了解 癌症治疗的生物学后果和评估操纵的可行性 用于治疗目的的线粒体信号通路。这一假设将在 遵循特定的目标。目的1是探索线粒体的功能调节和作用。 HNSCC细胞中的PKCε-ATAD3A复合体。目标2是为了说明潜在的机制 HNSCC细胞中ATAD3A依赖的线粒体ERK1/2激活。目标3是开发新的 通过共同抑制ATAD3A和EGFR控制HNSCC进展的治疗方法。 我们的首要目标是通过以下方式提高EGFR靶向治疗HNSCC的疗效 同时抑制ATAD3A介导的线粒体信号转导，肿瘤靶向 用于埃洛替尼/siRNA(抗ATAD3A)共给药的多功能纳米粒。结果来自 该项目将对新组合的设计和实施产生重大影响 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.