Neuroimmune Mechanisms of Cancer-Related Symptoms in Oral Squamous Cell Carcinoma

口腔鳞状细胞癌癌症相关症状的神经免疫机制

基本信息

批准号：
8863142
负责人：
Robert Dantzer
金额：
$ 43.33万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-19 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8863142
关键词：
Affect Animals Attenuated Behavioral Behavioral Symptoms Biological Response Modifiers Biology Brain Cancer Patient Cell Death Cells Cisplatin Communication Cytokine Signaling Cytotoxic Chemotherapy DNA Damage Deglutition Disorders Development Dioxygenases Enzymes Epidemic Event Fatigue Functional disorder Goals Human Papillomavirus Human papillomavirus 16 Immune Immune response Immune system Impaired cognition Implant Incidence Individual Inflammation Inflammation Mediators Inflammatory Inflammatory Response Intervention Kynurenine Left Malignant Neoplasms Measures Mediating Mental Depression Microglia Mixed Function Oxygenases Modality Modeling Molecular Moods Mus Neuraxis Neuroimmunomodulation Neurons Normal tissue morphology Operative Surgical Procedures Oral cavity Oropharyngeal Oropharyngeal Squamous Cell Carcinoma Pain Pathway interactions Patients Pattern Peripheral Pharyngeal structure Population Preventive Quality of life Radiation Radiation therapy Recruitment Activity Research Risk Role Running Signal Pathway Signal Transduction Sleep Disorders Societies Staging Symptoms Testing Time Toxic effect Treatment Efficacy Treatment-Related Cancer Tryptophan United States Food and Drug Administration Work behavioral response cancer therapy cell transformation chemoradiation chemotherapy cost daily functioning design experience improved indoleamine innovation male mouse model mouth squamous cell carcinoma neoplastic cell neuronal circuitry neurotoxic oral mucositis palliative prevent public health relevance relating to nervous system repaired response social tumor

项目摘要

DESCRIPTION (provided by applicant): Patients with human papilloma virus (HPV+)-related oropharyngeal squamous cell carcinoma (OPSCC) experience severe systemic symptoms including fatigue, depression, and cognitive dysfunction during the course of cancer therapy. These symptoms negatively affect quality of life and compromise their daily social and vocational functioning, even after cessation of therapy. The long-term goal of this project is to elucidate, using a syngeneic murine model of HPV+ OPSCC exposed to chemoradiation, how the tumor and cancer therapy induce symptoms and what can be done to prevent symptom development. Because of the strong analogy between cancer-related symptoms and the behavioral signs of inflammation-induced sickness, the working hypothesis is that the inflammatory response to HPV+ OPSCC and to cytotoxic therapy propagates to the brain and activates the neuronal circuitry of sickness. This hypothesis will be tested in 3 specific aims designed to: (1) characterize the association between the development of sickness and the time course of peripheral and central inflammation, and determine the status of microglia activation in mice implanted with HPV+ positive tumor cells and exposed to chemoradiation; (2) identify the molecular factors that cause tumor- and chemoradiation-associated sickness by focusing on triggers and mediators of inflammation, including damage-associated molecular patterns (DAMPs) and cytokine signaling pathways; and (3) determine whether activation of the kynurenine pathway downstream of cytokine signaling pathways contributes to the development of chemoradiation-induced sickness. Because the immune system of the host is involved in chemoradiation-induced clearance of OPSCC especially in HPV+ tumors, we will search for druggable targets in the chain of events leading from the release of DAMPs to the recruitment of neuronal circuits of sickness that do not compromise tumor clearance and survival. There is an increasing incidence rate of HPV+ OPSCC that contrasts with steady declines in HPV-OPSCC. HPV+ OPSCC predominantly affects individuals at peak productive points in their lives, with enormous costs to affected individuals and the society. Identification of means to alleviate symptom burden and facilitate the return to normal daily functioning will have an important positive individual and societal impact.

描述（由申请人提供）：患有人乳头瘤病毒（HPV+）相关口咽鳞状细胞癌（OPSCC）的患者在癌症治疗过程中会出现严重的全身症状，包括疲劳、抑郁和认知功能障碍，这些症状对生活质量产生负面影响。即使在停止治疗后，也会损害他们的日常社会和职业功能。该项目的长期目标是使用暴露的 HPV+ OPSCC 的同基因小鼠模型来阐明。由于癌症相关症状与炎症引起的疾病的行为体征之间有很强的相似性，因此工作假设是炎症反应与放化疗有关。 HPV+ OPSCC 和细胞毒性治疗传播到大脑并激活疾病的神经元回路。该假设将在 3 个具体目标中进行测试，旨在：（1）表征疾病发展与外周和中枢炎症时间进程之间的关联。，并确定植入 HPV+ 阳性肿瘤细胞并接受放化疗的小鼠中小胶质细胞的激活状态；(2) 通过关注炎症的触发因素和介质，包括损伤相关的分子模式，确定导致肿瘤和放化疗相关疾病的分子因素。 DAMPs）和细胞因子信号通路；（3）确定细胞因子信号通路下游的犬尿氨酸通路的激活是否有助于放化疗引起的疾病的发展，因为宿主的免疫系统参与放化疗引起的清除。特别是在 HPV+ 肿瘤中，我们将在从 DAMP 释放到疾病神经回路募集的一系列事件中寻找可用药的靶点，这些靶点不会影响肿瘤的清除和存活。 HPV+ OPSCC 的发病率不断增加。与 HPV-OPSCC 的稳定下降形成鲜明对比的是，HPV+OPSCC 主要影响处于生命高峰期的个体，给受影响的个人和社会带来巨大的代价。恢复正常的日常功能将对个人和社会产生重要的积极影响。