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

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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.