Autophagy-promoting NLRX1-TUFM complex and cancer cell resistance to cetuximab

描述（申请人提供）：少数具有博士学位的口腔颌面病理学家在免疫学和口腔生物学领域的学位，候选人寻求发展一个独立的研究生涯，重点是口腔，头颈部癌症的诊断和治疗。候选人一直是富有成效的，并在备受尊敬的同行评审期刊上发表了与此应用高度相关的主题。在领先的头颈外科科学家Robert Ferris博士的指导下，候选人在头颈部鳞状细胞癌（HNC）细胞中取得了新的发现，以支持这一应用。通过全面整合的五人委员会的协同指导，该委员会具有广泛的专业知识，涵盖该应用的各个方面，该奖项允许候选人开发癌症免疫学，内质网（ER）应激信号传导和翻译HNC研究的新实验技能和知识。在匹兹堡大学的一个著名的HNC计划中，额外的指导培训有助于高质量的翻译研究， 发展候选人的科学领导能力。HNC是第六常见的人类癌症，具有频繁的耐药性。表皮生长因子受体（EGFR）单克隆抗体西妥昔单抗在约20%的HNC患者中显示出有希望的治疗效果。西妥昔单抗通过抑制EGFR信号传导和激活靶向癌细胞的细胞免疫来抑制肿瘤生长。然而，80%的无应答率表明存在内在耐药机制。自噬已被证明被多种实体瘤劫持，以忍受治疗引起的痛苦。最近的研究表明，肿瘤细胞中的自噬诱导降低了它们对免疫效应细胞的易感性，并且自噬的抑制使HNC细胞对西妥昔单抗敏感。然而，缺乏对HNC细胞中自噬机制的机制性洞察使得该机制的靶向非常不特异且无效。我们的长期目标是利用参与自噬的分子来改善针对HNC的系统治疗。最近的一项研究揭示了一种以NLRX 1和TUFM蛋白为中心的促进自噬的线粒体蛋白复合物。我们假设通过靶向NLRX 1-TUFM复合物特异性抑制自噬，使HNC细胞对西妥昔单抗敏感。我们有三个目标：（1）我们将评估NLRX1-TUFM复合物在体外调节EGFR阻断效应中的作用;（2）我们将研究自噬在调节HNC患者对西妥昔单抗的反应中的作用;（3）我们将验证靶向NLRX1-TUFM的体内治疗潜力，并探索该复合物用于参与EGFR阻断诱导的自噬的机制。该项目的完成将为HNC细胞的自噬机制提供新的见解，并确定潜在的治疗靶点，以改善基于西妥昔单抗的治疗方案。

DESCRIPTION (provided by applicant): Among a few oral and maxillofacial pathologists with a Ph.D. degree in the field of Immunology and Oral Biology, the candidate seeks to develop an independent research career focusing on the diagnosis and treatment of oral, head & neck cancer. The candidate has been continuously productive, and published in well-respected peer-reviewed journals on the topics highly relevant to this application. Under the mentorship of Dr. Robert Ferris, a leading head and neck surgeon-scientist, the candidate has made novel discoveries in head and neck squamous cell carcinoma (HNC) cells to support this application. With synergistic mentorship from a fully integrated five-member committee with broad expertise to cover every aspect of this application, this award allows the candidate to develop new experimental skills and knowledge of cancer immunology, endoplasmic reticulum (ER) stress signaling, and translational HNC research. Additional mentored training in a prominent HNC program, at the University of Pittsburgh, is conductive for high quality translational research and the development of scientific leadership skills of the candidate. HNC is the sixth most common human cancers with frequent resistance. The epidermal growth factor receptor (EGFR) monoclonal antibody, cetuximab, shows promising therapeutic efficacy in about 20% of HNC patients. Cetuximab suppresses tumor growth by inhibition of EGFR signaling and activation of cellular immunity targeting cancer cells. However, the 80% non-response rate suggests an intrinsic resistance mechanism. Autophagy has been shown to be hijacked by multiple solid tumors to endure therapy-induced inflictions. Recent study shows that autophagy induction in tumor cells dampens their susceptibility to immune effector cells, and that inhibition of autophagy sensitizes HNC cells to cetuximab. However, the lack of mechanistic insight into the autophagy machinery in HNC cells renders the targeting of this mechanism remarkably unspecific and ineffective. Our long-term goal is to leverage molecules involved in autophagy to improve systemic therapy against HNC. A recent study reveals an autophagy-promoting mitochondrial protein complex centering on NLRX1 and TUFM proteins. We hypothesize that specific inhibition of autophagy, by targeting the NLRX1-TUFM complex, sensitizes HNC cells to cetuximab. Three aims are put in place: (1) we will assess the role of NLRX1-TUFM complex in modulating the effects of EGFR blockade in vitro; (2) we will investigate the role of autophagy in modulating HNC patients' responses to cetuximab; (3) we will validate the therapeutic potential of targeting NLRX1-TUFM in vivo, and explore the mechanisms this complex employs to engage EGFR blockade-induced autophagy. Completion of this project will provide novel insights into the autophagy machinery of HNC cells and identify potential therapeutic targets to improve a cetuximab-based regimen.