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.

项目摘要头颈部鳞状细胞癌（HNC）几乎普遍的症状是与癌症相关的疼痛。口服腔和口咽癌比其余的头颈部解剖部位更痛苦。与HNC相关的疼痛经常会产生对吗啡的抵抗力，很少有策略可有效疼痛管理产生抵抗。此外，不可避免的吗啡剂量升级导致便秘，恶心，镇静，口干和Myoclonus，这大大降低了患者的质量生活。最近的研究还表明，吗啡具有不良的免疫抑制特征。通过对父级R01奖的支持，我们发现I型干扰素签名是免疫原性的基础 HNC的第二个贡献，以理解对I型干扰素的致癌性抑制促进衔接蛋白的快速营业额，干扰素基因的刺激剂（STING）。除了刺痛激动剂在重编程抗原呈递细胞以跨越主要CD8+细胞毒性T-的潜力淋巴细胞更有效，我们最近发现了刺痛激动剂的意外而强大的功能促进镇痛。在Sting-type-i干扰素途径中明确显示的宿主明显显示升高伤害感受器的兴奋性。我们发现，HNC启动的常见驱动器癌基因抑制在肿瘤微环境中刺痛并导致I型干扰素剥夺。在此补充提案中，我们将提供变革性的证据，以利用I型干扰素来管理HNC相关的，抗吗啡的疼痛。为了实现这一目标，我们生成了具有高的新颖而严格的HNC模型忠诚与人类HNC突变特征相似。我们将整合全面的建模，行为研究和单细胞技术识别用于HNC疼痛管理的非阿片类药物。