IDENTIFYING THE ROLE OF INFLAMMATORY CYTOKINES IN SYMPTOM PRODUCTION

确定炎症细胞因子在症状产生中的作用

• 批准号: 8381058
• 负责人: CHARLES S CLEELAND
• 金额: $ 29.84万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8381058
• 关键词: Accounting; Active Biological Transport; Acute; Address; Affect; Affective Symptoms; Allogenic; Animal Model; Animals; Anorexia; Antibodies; Autologous Bone Marrow Transplantation; Autologous Stem Cell Transplantation; Autologous Transplantation; Behavior; Biological Assay; Biological Markers; Biological Response Modifiers; Biology; Biometry; Blood - brain barrier anatomy; Bone Marrow Transplantation; Bone Pain; Bortezomib; Brain; C-reactive protein; Cancer Cluster; Cancer Patient; Cancer Survivor; Cell Count; Cessation of life; Cities; Clinical; Clinical Trials; Control Groups; Controlled Clinical Trials; Curcumin; Cytokine Network Pathway; Cytokine Suppression; Data; Desire for food; Detection; Development; Disease; Disease Progression; Disease remission; Distress; Dose; Effectiveness; Equilibrium; Equipment and supply inventories; Esthesia; Exhibits; Fatigue; Foundations; Future; Hand; Health; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; High Dose Chemotherapy; Hyperalgesia; Individual; Inflammation; Inflammatory; Integration Host Factors; Interleukin-1; Interleukin-6; Interleukins; International; Knowledge; Learning; Leukocytes; Link; Literature; Maintenance Therapy; Malignant Neoplasms; Measurable; Measures; Methods; Modeling; Molecular; Morbidity - disease rate; Multiple Myeloma; NF-kappa B; Neoadjuvant Therapy; Nerve Fibers; Neuropathy; Newly Diagnosed; Numbness; Onset of illness; Opioid; Outcome; Outcome Measure; Pain; Pathway interactions; Patient Self-Report; Patients; Perception; Phase; Placebo Control; Placebos; Plasma Cells; Population; Prevalence; Preventive; Production; Publishing; Quality of life; Randomized; Randomized Clinical Trials; Reducing Agents; Reporting; Research; Risk; Role; Sampling; Sensory; Serum; Severities; Sleep; Sleep Disorders; Sleep disturbances; Statistical Models; Sum; Supportive care; Symptoms; Testing; Texas; Thalidomide; Time; Toxic effect; Transplantation; Treatment-Related Cancer; Tumor Burden; Tumor Markers; Tumor Necrosis Factor-alpha; University of Texas M D Anderson Cancer Center; Voice; afferent nerve; analog; arm; base; bone fatigue; burden of illness; cancer therapy; cytokine; data management; design; driving force; experience; foot; improved; inhibitor/antagonist; interest; lenalidomide; method development; multiple myeloma M Protein; novel; overexpression; painful neuropathy; phase 2 study; prevent; primary outcome; randomized placebo controlled trial; response; survivorship; symptom management; therapeutic target; therapy development; tool; transplant registry; tumor necrosis factor-alpha inhibitor; tumor progression

Multiple myeloma (MM) is an incurable but treatable cancer. Patients with MM patients suffer from multiple symptoms caused by their disease and by aggressive treatment, such as autologous transplantation (AuSCT) and novel agents used for induction or maintenance therapy. Symptoms create a "symptom burden" that cause distress and that can compromise patient's function and cause treatment delays. There is increasing evidence that many of these symptoms may be caused by the deregulation of inflammatory cytokines and their precursors. Built on a large body of literature relating "sickness behavior" in animals (including pain, sleep disorder, reduced appetite, and decreased activity), we have developed the hypothesis that many cancer-related symptoms might be improved by modulating inflammatory pathways. We and others have shown that circulating inflammatory cytokines (such as interleukin (IL)-6 and TNF) are strongly linked to symptom severity. For example, we have shown that increased IL-6 is related to the severity of a cluster of symptoms during AuSCT in patients with MM. What is not known is whether suppression of these cytokines might reduce or prevent the prevalence and severity of treatment-related symptoms. The objectives of this project are: (i) To use hierarchical dynamic modeling to examine the hypothesis that increases in the levels of inflammatory cytokines and NF-KB drive increases in symptom development in patients with MM that are related to status of disease as well as during cancer therapy (Specific Aims i, 2, 3); (2) We also will use anticytokine agents (cytokine IL-6 antibody CNTO 328) and an NF-KB inhibitor (curcumin) in phase 2 placebo-controlled randomized clinical trials, to test the hypothesis that reduction of specific inflammatory cytokine levels and/or NF-KB activation will reduce symptom expression. This provides an experimental test of the role of specific inflammatory cytokines (IL-i, IL-6, and TNF-a) and their precursors (NF-KB) in symptom development (Specific Aims 2,3). Taken together, these Aims should provide a strong test of our central hypothesis that a causal relationship exists between inflammatory cytokines and symptom production in patients with MM. Our long-term objectives are to characterize the basic mechanisms underlying symptom burden (with particular focus on cytokines and immune mediators), and to provide a rationale for mechanism-driven symptom management. Having the ability to reduce symptom burden or even prevent these consequences from therapy would be of potential benefit to thousands of cancer patients by improving the tolerability of treatment and the quality of their survivorship. PERFORMANCE SITE(S) (organization, city, state) The University of Texas M. D. Anderson Cancer Center Houston, Texas Page 157

多发性骨髓瘤（MM）是一种无法治愈但可治疗的癌症。MM患者患有 由疾病和积极治疗（如自体移植）引起的多种症状 （AuSCT）和用于诱导或维持疗法的新型药剂。症状产生一种“症状 这是一种“负担”，会造成痛苦，并可能损害患者的功能，导致治疗延误。那里 越来越多的证据表明，这些症状中的许多可能是由炎症反应失调引起的。 细胞因子及其前体。建立在大量关于动物“病态行为”的文献基础上 （包括疼痛、睡眠障碍、食欲下降和活动减少），我们提出了假设， 许多癌症相关的症状可以通过调节炎症途径来改善。我们和 其他研究表明，循环中的炎性细胞因子（如白细胞介素（IL）-6和TNF）强烈地 与症状严重程度相关。例如，我们已经表明，IL-6的增加与糖尿病的严重程度有关。 MM患者AuSCT期间的一系列症状。目前尚不清楚是否抑制这些症状 细胞因子可以减少或预防治疗相关症状的发生率和严重程度。 本项目的目标是：（i）使用分层动态模型来检查 炎症细胞因子和NF-κ B水平的增加驱动症状增加的假设 MM患者中与疾病状态以及癌症治疗期间相关的发展 （具体目的i，2，3）;（2）我们还将使用抗细胞因子剂（细胞因子IL-6抗体CNTO 328）和抗肿瘤药物（抗肿瘤药物）。 NF-κ B抑制剂（姜黄素）在2期安慰剂对照随机临床试验中，以检验假设 特异性炎性细胞因子水平和/或NF-κ B活化的降低将减轻症状 表情这提供了特异性炎性细胞因子（IL-1、IL-6和IL-10）的作用的实验测试。 TNF-α）及其前体（NF-κ B）在症状发展中的作用（特异性目的2，3）。 总之，这些目标应该为我们的中心假设提供了强有力的检验，即因果关系 MM患者的炎症细胞因子与症状的产生存在相关性。 我们的长期目标是描述症状负担的基本机制（ 特别关注细胞因子和免疫介质），并为机制驱动的 症状管理有能力减轻症状负担甚至预防这些后果 通过改善癌症患者的生活质量， 治疗的耐受性和生存质量。 履约地点（组织、城市、州） 德克萨斯大学M. D.安德森癌症中心 德克萨斯州休斯顿 第157页