Identifying non-opioid strategies to manage oral cancer pain

确定非阿片类药物策略来控制口腔癌疼痛

• 批准号: 10617001
• 负责人: Christopher Ryan Donnelly
• 金额: $ 25万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10617001
• 关键词: Absence of pain sensation; Adaptor Signaling Protein; Adjuvanticity; Advanced Development; Agonist; Analgesics; Anatomy; Antigen-Presenting Cells; Award; Behavioral; Bone Marrow; Cells; Chronic; Complex; Constipation; DNA; Disease; Dose; Double-Stranded RNA; Formulation; G-Protein-Coupled Receptors; Gene Activation; Genomics; Goals; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Human; IRF3 gene; Immunization; Immunosuppression; Immunotherapy; Implant; Inflammasome; Infrastructure; Interferon Type I; Interferon-beta; Interferons; Interleukin-6; Intrathecal Injections; KRAS2 gene; Knowledge; Lead; Location; Malignant Neoplasms; Measures; Modeling; Morphine; Mus; Mutation; Myoclonus; Nausea; Nociception; Nociceptors; Oncogenes; Oncogenic; Opioid; Oral cavity; Orofacial Pain; Pain; Pain management; Parents; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern recognition receptor; Persistent pain; Pharmacology; Poly I-C; Potassium; Progression-Free Survivals; Quality of life; Receptor Activation; Recurrence; Refractory; Regulation; Reproducibility; Resistance; Resistance development; Resolution; Rest; Sedation procedure; Seminal; Series; Signal Transduction; Smoking; Specificity; Stimulator of Interferon Genes; Surveys; Symptoms; TBK1 gene; TLR2 gene; TLR3 gene; TLR4 gene; TP53 gene; Testing; Tongue; Tumor Burden; Tumor-infiltrating immune cells; Unresectable; Xerostomia; addiction; anti-PD-L1; anti-tumor immune response; base; behavioral study; cancer pain; chemotherapy; cytotoxic CD8 T cells; debilitating pain; deprivation; head and neck cancer patient; immune checkpoint blockade; immunogenicity; implantation; improved; in vivo; irradiation; macrophage; malignant mouth neoplasm; malignant oropharynx neoplasm; morphine tolerance; mu opioid receptors; neoplastic cell; non-opioid analgesic; novel; pain model; pain relief; programs; public health relevance; reduce symptoms; response; reward circuitry; side effect; single cell technology; tumor; tumor microenvironment

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.

项目总结 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。口头的 口腔癌和口咽癌甚至比头颈部的其他解剖部位更痛苦。 HNC相关性疼痛经常对吗啡产生抵抗力，有效的治疗策略很少 在他们产生抵抗力后的疼痛管理。此外，不可避免的吗啡剂量增加会导致 便秘、恶心、镇静、口干和肌阵挛，这些都会显著降低患者的生活质量 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 支持父母R01奖，我们发现I型干扰素签名支持免疫原性 并为理解HNC对I型干扰素的致癌抑制做出了开创性的贡献。 促进一种适配器蛋白的快速周转，即干扰素基因的刺激物(STING)。除 STING激动剂对抗原提呈细胞重新编程以跨越初始CD8+细胞毒T细胞的潜力 更有效的淋巴细胞，我们最近发现了一种意想不到的强大的刺痛激动剂的功能 在促进止痛方面。缺乏刺痛-I型干扰素途径的宿主显示出显著的 伤害性感受器兴奋性升高。我们已经发现HNC启动抑制的共同驱动癌基因 刺痛并导致肿瘤微环境中的I型干扰素缺失。在这份补充提案中， 我们将提供变革性的证据来利用I型干扰素来管理HNC相关的、 耐吗啡的疼痛。为了实现这一目标，我们生成了新的和严格的HNC模型，具有高 与人类HNC突变特征的保真度相似。我们将综合建模、行为 研究和单细胞技术，以确定用于HNC疼痛控制的非阿片类药物。