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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

基本信息

批准号：
8876408
负责人：
BRUCE E. MAGUN
金额：
$ 38.56万
依托单位：
MGH INSTITUTE OF HEALTH PROFESSIONS
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-06 至 2017-06-30
项目状态：
已结题

项目摘要

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）：接受细胞毒性化疗药物治疗的癌症患者经常会出现一系列症状，包括疲劳、食欲下降、睡眠不安、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)）与化疗药物类别无关，对身体机能和生活质量 (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，为了制定成功的预防或治疗 CTRS 的策略，我们需要在分子和细胞水平上了解 CTRS 的病因机制。我们假设机制上不同的细胞毒性化疗药物会触发 CTRS，因为它们具有增加促炎细胞因子 IL-1b 产生的共同能力。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，即对感染或 IL-1b 全身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，我们发现 CTRS 峰值与 IL-1β 的全身增加相关。第三，使用小鼠巨噬细胞作为模型系统，我们证明了机制上不同的细胞毒性化疗药物可以通过三步过程刺激IL-1β的产生和分泌。第一个信号通过化疗药物的细胞毒性作用传递至巨噬细胞，通过释放 Toll 样受体 (TLR) 的内源性激活剂，使这些细胞直接表达 pro-IL-1b。第二个信号来自 ZAK 的激活，ZAK 是一种由化疗药物激活的 MAP3K，可延长并强化 JNK 和 p38 MAPK 的激活，并与 NF-kB 协同作用以放大 pro-IL-1b 的表达。化疗药物传递的第三个信号通过诱导 NLRP3 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，化疗药物对 IL-1β 的分泌主要取决于 NLRP3 炎性体成分 ASC、CASP1 和 NLRP3。这项为期 4 年的研究的目的是确定机制上不同的细胞毒性化疗药物是否会触发 CTRS，因为它们具有增加 IL-1b 产生的共同能力。如果得到证实，IL-1b 信号级联的各个步骤可能会为预防或治疗 CTRS 的干预提供重要目标。为了检验我们的假设，我们提出以下目标：1) 确定机械上不同的细胞毒性化疗药物诱导炎症细胞因子的分子机制 2) 确定阻断 ZAK 信号传导是否会降低 CTRS。 3) 确定 NLRP3 炎性体的破坏是否会降低 CTRS。