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.

项目概要 头颈鳞状细胞癌 (HNC) 的一个几乎普遍的症状是与癌症相关的疼痛。口服 腔癌和口咽癌甚至比头颈部其他解剖部位更痛苦。 HNC 相关疼痛经常对吗啡产生耐药性，并且很少有策略可用于有效治疗吗啡。 当他们产生抵抗力后进行疼痛管理。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，这些都会大大降低患者的治疗质量 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 在母公司 R01 奖的支持下，我们发现 I 型干扰素特征支撑了免疫原性 HNC 的研究人员，对 I 型干扰素致癌抑制的理解做出了开创性贡献 促进接头蛋白、干扰素基因刺激物 (STING) 的快速周转。除了 STING 激动剂在重新编程抗原呈递细胞以交叉引发 CD8+ 细胞毒性 T- 方面的潜力 更有效地抑制淋巴细胞，我们最近发现了 STING 激动剂意想不到但强大的功能 在促进镇痛方面。缺乏 STING-I 型干扰素途径的宿主表现出显着的 伤害感受器兴奋性升高。我们发现 HNC 启动的常见驱动癌基因会抑制 STING 并导致肿瘤微环境中 I 型干扰素剥夺。在这个补充提案中， 我们将提供变革性证据，利用 I 型干扰素来管理 HNC 相关的、 吗啡抵抗性疼痛。为了实现这一目标，我们生成了新颖且严格的 HNC 模型，具有高 与人类 HNC 突变特征保真相似。我们将综合建模、行为 研究和单细胞技术来识别用于 HNC 疼痛管理的非阿片类药物。