IDENTIFYING THE ROLE OF INFLAMMATORY CYTOKINES IN SYMPTOM PRODUCTION

多发性骨髓瘤(MM)是一种无法治愈的癌症。多发性骨髓瘤患者患有 由他们的疾病和积极的治疗引起的多种症状，如自体移植 (AuSCT)和用于诱导或维持治疗的新型药物。症状会产生一种“症状” 造成痛苦的“负担”，这可能会损害患者的功能，导致治疗延误。 越来越多的证据表明，这些症状中的许多可能是由放松对炎症性疾病的管制引起的 细胞因子及其前体。建立在大量有关动物“疾病行为”的文献基础上 (包括疼痛、睡眠障碍、食欲下降和活动减少)，我们发展了这个假说 许多与癌症相关的症状可能会通过调节炎症途径而得到改善。我们和 其他研究表明，循环中的炎性细胞因子(如白介素6和肿瘤坏死因子)对 与症状严重程度有关。例如，我们已经证明，IL-6的增加与急性胰腺炎的严重程度有关 MM患者在AuSCT期间的一系列症状尚不清楚是否抑制了这些症状 细胞因子可以减少或预防与治疗相关的症状的流行和严重程度。 本项目的目标是：(I)使用分层动态建模来检查 炎性细胞因子水平升高和核因子-KB驱动增加症状增加的假说 多发性骨髓瘤患者的发展与疾病状态及癌症治疗有关 (2)我们还将使用抗细胞因子药物(细胞因子IL-6抗体CNTO 328)和 2期安慰剂对照随机临床试验中的核因子-KB抑制剂(姜黄素)，以验证这一假设 特异性炎性细胞因子水平的降低和/或核因子-kB的激活将减轻症状 表情。这为特定的炎性细胞因子(IL-I、IL-6和 肿瘤坏死因子-α)及其前体(核因子-kB)在症状发展中的作用(特异性目标2，3)。 总而言之，这些目标应该会有力地检验我们的核心假设，即一个因果关系 MM患者的炎性细胞因子与症状产生之间存在相关性。 我们的长期目标是确定症状负担背后的基本机制(与 特别关注细胞因子和免疫介体)，并为机制驱动提供理论基础 症状管理。有能力减轻症状负担，甚至预防这些后果 通过改善治疗，将对成千上万的癌症患者有潜在的好处 治疗的耐受性和生存质量。 演出现场(S)(组织、市、州) 德克萨斯大学安德森癌症中心 德克萨斯州休斯顿 第157页

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