Identifying non-opioid strategies to manage oral cancer pain

项目摘要 头颈部鳞状细胞癌（HNC）的一个几乎普遍的症状是癌症相关的疼痛。口服 口腔癌和口咽癌甚至比头颈部解剖部位的其它部位更痛。 HNC相关的疼痛经常对吗啡产生耐药性，并且很少有有效的治疗策略。 疼痛管理后，他们发展阻力。此外，不可避免的吗啡剂量增加导致 便秘、恶心、镇静、口干和肌阵挛，这大大降低了患者的生活质量。 生活最近的研究还表明，吗啡具有不良的免疫抑制特性。通过 在亲本R 01奖的支持下，我们发现I型干扰素特征支持免疫原性， HNC的，并作出了开创性的贡献，以了解致癌抑制的I型干扰素， 促进接头蛋白的快速周转，干扰素基因刺激物（STING）。除了有 STING激动剂在重编程抗原呈递细胞以交叉引发CD 8+细胞毒性T细胞中的潜力 我们最近发现了STING激动剂的一种意想不到的强大功能， 促进镇痛。在STING-I型干扰素途径中缺乏的肿瘤细胞表现出显著的 伤害感受器兴奋性升高我们已经发现，HNC启动的共同驱动癌基因抑制了HNC的启动。 STING并导致肿瘤微环境中的I型干扰素剥夺。在这一补充建议中， 我们将提供变革性的证据，以利用I型干扰素管理HNC相关， 吗啡抵抗性疼痛为了实现这一目标，我们生成了新颖而严格的HNC模型， 与人类HNC突变特征的保真度相似性。我们将综合建模，行为 研究和单细胞技术，以确定用于HNC疼痛管理的非阿片类药物。

PROJECT SUMMARY An almost universal symptom of head and neck squamous cell carcinoma (HNC) is cancer-related pain. Oral cavity and oropharyngeal cancers are even more painful than the rest of the head and neck anatomic sites. HNC-associated pain frequently develops resistance to morphine and few strategies are available for effective pain management after they develop resistance. In addition, the inevitable morphine dose escalation leads to constipation, nausea, sedation, dry mouth, and myoclonus, which substantially decrease the patient’s quality of life. Recent studies have also shown that morphine has undesirable immunosuppressive features. Through the support of the parent R01 award, we have found that type-I interferon signatures underpin the immunogenicity of HNC and made seminal contributions to the understanding of oncogenic suppression of type-I interferons by promoting the rapid turnover of an adaptor protein, stimulator of interferon genes (STING). In addition to the potential of STING agonists in reprograming the antigen-presenting cells to cross prime CD8+ cytotoxic T- lymphocytes more effectively, we recently uncovered an unexpected yet powerful function of STING agonists in promoting analgesia. Hosts that are deficient in the STING-type-I interferon pathway show significantly elevated nociceptor excitability. We have found that common driver oncogenes for HNC initiation suppress STING and lead to type-I interferon deprivation in the tumor microenvironment. In this supplement proposal, we will provide transformative evidence to leverage type-I interferons for the management of HNC-associated, morphine-resistant pain. To achieve this goal, we have generated novel and rigorous HNC models with high fidelity resemblance to human HNC mutational features. We will integrate comprehensive modeling, behavior studies, and single-cell technologies to identify non-opioid agents for HNC pain management.