Clinical study to evaluate the methylation signature of head and neck squamous cell carcinoma pain

摘要 拟议的研究和职业发展计划旨在促进我的发展之路 成为一名独立的外科医生科学家，专注于高度转化的头颈部鳞状细胞 癌（HNSCC）研究。我早期的研究生涯致力于探索表观遗传机制 (i.e., DNA甲基化）的HNSCC疼痛，一个研究领域，否则就被忽视了。这项建议 建立在我以前的研究中，我确定疼痛介导基因的超甲基化有助于 HNSCC疼痛，以及低甲基化剂治疗HNSCC疼痛。职业发展计划 是精心组织，通过一系列的课程，全国会议， 和我的导师团队开会完成K23课程后，我将做好充分准备， 通过R01机制提供独立的研究资金，这将支持我的转化研究计划 专注于头颈部癌症疼痛的治疗 在这个建议中，我采取了一种系统的方法来鉴定在严重的乳腺癌患者中甲基化的基因， HNSCC疼痛。在目标1中，我前瞻性地招募HNSCC患者，用经验证的疼痛量化他们的疼痛水平， 问卷调查，并收集他们的癌症组织进行全基因组甲基化阵列分析。我会分析 甲基化数据，并确定了一套高甲基化的基因在患者的严重疼痛。我已经证明 通过初步研究，我使用了HNSCC中现有的甲基化数据， 患者以确定一系列高甲基化基因。这些基因中的许多以前没有被关联 疼痛的处理。在目标2中，我专注于一个高甲基化基因，并确定腺病毒治疗是否 重新表达该基因在临床前模型中产生抗伤害感受。该项目具有影响力，因为它 探索了一种很大程度上未知的疼痛机制。结果将建立甲基化特征 HNSCC疼痛。这些基因可以用基因疗法或低甲基化剂靶向治疗 HNSCC疼痛，提供非阿片类药物替代品，并使研究具有临床相关性，特别是与 当前的鸦片危机 我的指导和咨询团队由在以下方面拥有专业知识的个人组成： 转化和临床研究，特别是在癌症，疼痛，生物信息学和药物发现领域， 所有这些都对拟议的研究至关重要。我有受保护的时间实验室空间启动资金 和人员支持。职业发展计划和拟议的研究将使我更接近实现我的 职业目标是开发高效的头颈癌疼痛治疗方法。

ABSTRACT The proposed research and career development plan have been designed to facilitate my path toward becoming an independent surgeon scientist focused on highly translational head and neck squamous cell carcinoma (HNSCC) research. I have devoted my early research career to exploring epigenetic mechanisms (i.e., DNA methylation) of HNSCC pain, an area of research that has otherwise gone unnoticed. This proposal builds on my previous research in which I determine that hypermethylation of pain-mediating genes contribute to HNSCC pain in patients, and that hypomethylating agents treat HNSCC pain. The career development plan is carefully structured to hone my expertise in clinical research through a series of courses, national meetings, and meetings with my mentorship team. Upon completion of the K23, I will be well-prepared to apply for independent research funding through an R01 mechanism, which will support my translational research program focused on treatments for head and neck cancer pain. In this proposal I take a systematic approach to identify genes that are methylated in patients with severe HNSCC pain. In Aim 1 I prospectively enroll HNSCC patients, quantify their pain levels with validated pain questionnaires, and collect their cancer tissue for analysis with a genome-wide methylation array. I will analyze the methylation data and identify a suite of hypermethylated genes in patients with severe pain. I have proven feasibility of this approach through preliminary studies, in which I used existing methylation data in HNSCC patients to identify a list of hypermethylated genes. Many of these genes have not previously been associated with pain processing. In Aim 2, I focus on one hypermethylated gene and determine whether adenovirus therapy to re-express the gene produces antinociception in the preclinical model. The project is impactful because it explores a pain mechanism that is largely unknown. The results will establish the methylation signature of HNSCC pain. These genes could be targeted with either gene therapy or hypomethylating agents to treat HNSCC pain, offering non-opioid alternatives and making the research clinically relevant, especially with the current opioid crisis. My mentorship and advisory team is comprised of individuals who have expert knowledge in all aspects of translational and clinical research, specifically in the areas of cancer, pain, bioinformatics, and drug discovery, all of which are critical for the proposed research. I receive protected time, laboratory space, start-up funding, and personnel support. The career development plan and proposed research will bring me closer to realizing my career goal of developing highly effective treatments for head and neck cancer pain.