Targeting IL-1beta as a strategy for symptom control in cancer

以 IL-1beta 为靶点作为癌症症状控制策略

• 批准号: 8541060
• 负责人: BRUCE E. MAGUN
• 金额: $ 37.68万
• 依托单位: MGH INSTITUTE OF HEALTH PROFESSIONS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-06 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8541060
• 关键词: Affect; Anemia; Behavior; Biological Models; Body Composition; CASP1 gene; Cancer Patient; Cells; Complex; Depressed mood; Desire for food; Fatigue; Goals; Infection; Inflammatory; Intervention; MAP Kinase Gene; MAPK14 gene; MAPK8 gene; Malaise; Malignant Neoplasms; Molecular; Mus; NF-kappa B; Pain; Patients; Pharmaceutical Preparations; Physical Function; Physiological; Prevention; Process; Production; Quality of life; Signal Transduction; Sleep; Sleep disturbances; Symptoms; Testing; Thinking; Tissues; Toll-like receptors; Treatment-Related Cancer; base; cancer care; chemotherapeutic agent; chemotherapy; cytokine; cytotoxic; experience; inhibitor/antagonist; macrophage; mouse model; novel strategies; prevent; response; tumor

DESCRIPTION (provided by applicant): Cancer patients undergoing treatment with cytotoxic chemotherapeutic agents often experience a constellation of symptoms, which include fatigue, decreased appetite, disturbed sleep, changes in body composition, difficulty thinking, pain, and depressed mood. These symptoms, hereafter referred to as cancer treatment related symptoms (CTRS), occur independently of chemotherapy drug class and have a profound effect on physical functioning and quality of life (QOL) , making their prevention and/or treatment essential components of cancer care. We propose that in order to develop successful strategies to prevent or treat CTRS, we need to understand the etiological mechanisms of CTRS at molecular and cellular levels. We hypothesize that mechanistically distinct cytotoxic chemotherapeutic agents trigger CTRS because they share a common ability to increase the production of the pro-inflammatory cytokine IL-1b. There are several lines of evidence that support our hypothesis. First, CTRS are remarkably similar to the symptoms associated with sickness behavior, the expected physiological response to infection or tissue damage caused by systemic increases in IL-1b. Second, in a mouse model of CTRS we have shown that peak CTRS are associated with systemic increases in IL-1beta. Third, using murine macrophages as a model system, we have shown that mechanistically distinct cytotoxic chemotherapeutic agents can stimulate IL-1beta production and secretion in a 3-step process. The first signal, delivered to macrophages by the cytotoxic effects of the chemotherapeutic agent, primes these cells to express pro-IL-1b directly and through release of endogenous activators of Toll-like receptors (TLRs). The second signal results from the activation of ZAK, a MAP3K activated by the chemotherapeutic agent, that prolongs and intensifies the activation of JNK and p38 MAPK and synergizes with NF-kB to amplify the expression of pro-IL-1b. The third signal delivered by chemotherapeutic agent converts pro-IL-1b to its biologically active form IL-1b by inducing the formation of the NLRP3 inflammasome complex. Importantly, secretion of IL-1beta in response to the chemotherapeutic agent depends critically on the NLRP3 inflammasome components ASC, CASP1, and NLRP3. The purpose of this 4-year study is to determine whether mechanistically distinct cytotoxic chemotherapeutic agents trigger CTRS because they share a common ability to increase the production of IL-1b. If proven, the various steps of the IL-1b signaling cascade may provide important targets for intervention to prevent or treat CTRS. To test our hypothesis we propose the following aims: 1) Determine the molecular mechanisms underlying the induction of inflammatory cytokines by mechanistically distinct cytotoxic chemotherapeutic agents 2) Determine whether blocking ZAK Signaling reduces CTRS. 3) Determine whether disruption of the NLRP3 inflammasome reduces CTRS.

描述（由申请人提供）：接受细胞毒性化疗剂治疗的癌症患者通常会出现一系列症状，包括疲劳、食欲下降、睡眠障碍、身体成分变化、思维困难、疼痛和情绪低落。这些症状（以下称为癌症治疗相关症状（CTRS））的发生与化疗药物类别无关，并对身体功能和生活质量（QOL）产生深远影响，使其预防和/或治疗成为癌症护理的重要组成部分。我们建议，为了开发成功的策略来预防或治疗CTRS，我们需要了解CTRS的分子和细胞水平的发病机制。我们假设，不同的细胞毒性化疗药物触发CTRS的机制，因为他们有一个共同的能力，增加生产的促炎细胞因子IL-1b。有几条证据支持我们的假设。首先，CTRS与疾病行为相关的症状非常相似，这是对感染或由IL-1b全身性增加引起的组织损伤的预期生理反应。其次，在CTRS小鼠模型中，我们已经证明CTRS峰值与IL-1 β的全身性增加相关。第三，使用小鼠巨噬细胞作为模型系统，我们已经表明，机制不同的细胞毒性化疗药物可以刺激IL-1 β的生产和分泌在一个3步的过程。通过化疗剂的细胞毒性作用递送至巨噬细胞的第一个信号使这些细胞直接和通过Toll样受体（TLR）的内源性激活剂的释放而引发表达pro-IL-1b。第二个信号来自ZAK的激活，ZAK是一种由化疗剂激活的MAP 3 K，其抑制并增强JNK和p38 MAPK的激活，并与NF-κ B协同作用以放大pro-IL-1b的表达。由化疗剂递送的第三信号通过诱导NLRP 3炎性体复合物的形成将pro-IL-1b转化为其生物活性形式IL-1b。重要的是，响应于化疗剂的IL-1 β的分泌主要取决于NLRP 3炎性体组分ASC、CASP 1和NLRP 3。这项为期4年的研究的目的是确定是否机制不同的细胞毒性化疗药物触发CTRS，因为他们有一个共同的能力，增加IL-1b的生产。如果得到证实，IL-1b信号级联的各个步骤可能为预防或治疗CTRS的干预提供重要靶点。为了检验我们的假设，我们提出了以下目标：1）确定由机械上不同的细胞毒性化疗剂诱导炎性细胞因子的分子机制2）确定阻断ZAK信号传导是否减少CTRS。3)确定NLRP 3炎性体的破坏是否会降低CTRS。