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

基本信息

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
项目类别：
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

项目摘要

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癌症相关的口腔疼痛。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。此外，不可避免的吗啡剂量增加会导致出现耐药性。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最近的研究还表明吗啡具有不良的免疫抑制功能。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、干扰素基因刺激剂 (STING) 的快速周转。 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作用。我们发现 HNC 启动的常见驱动癌基因会抑制伤害感受器兴奋性。 STING 并导致肿瘤微环境中的 I 型干扰素剥夺。我们将提供变革性证据，利用 I 型干扰素来管理 HNC 相关的、为了实现这一目标，我们生成了新颖且严格的 HNC 模型。与人类 HNC 突变特征的保真度相似我们将整合综合建模、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。