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

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通常会出现一系列症状，包括疲劳、食欲下降、睡眠紊乱、身体成分改变、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），独立于化疗药物类别而发生，对身体功能和生活质量（QOL）有深远影响，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，为了制定成功的策略来预防或治疗CTRS，我们需要在分子和细胞水平上了解CTRS的病因机制。我们假设机制不同的细胞毒性化疗药物触发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、对感染的预期生理反应或由IL-1b全身性升高引起的组织损伤相关的症状非常相似。其次，在小鼠CTRS模型中，我们已经表明，CTRS峰值与全身il -1 β的增加有关。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通过三步过程刺激il -1 β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给巨噬细胞，使这些细胞直接表达亲il -1b，并通过释放内源性toll样受体（TLRs）激活剂。第二个信号来自于ZAK的激活，ZAK是一种被化疗药物激活的MAP3K，它延长并加强了JNK和p38 MAPK的激活，并与NF-kB协同放大了pro-IL-1b的表达。化疗药物传递的第三个信号是通过诱导NLRP3炎性体复合物的形成，将亲IL-1b转化为具有生物活性的IL-1b。重要的是，il -1 β的分泌对化疗药物的反应主要取决于NLRP3炎症小体成分ASC、CASP1和NLRP3。这项为期4年的研究的目的是确定机制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为干预预防或治疗CTRS提供重要靶点。为了验证我们的假设，我们提出以下目标：1)确定机制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。

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.