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

描述(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、睡眠障碍、身体成分变化、思考困难、疼痛和情绪低落。这些症状，以下称为癌症治疗相关症状(CTR)，独立于化疗药物类别出现，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。我们认为，为了开发成功的预防或治疗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，机械上不同的细胞毒性化疗药物触发CTRS是因为它们具有共同的能力，即增加促炎细胞因子IL-1b的产生。有几条证据支持我们的假设。首先，CTR与疾病行为相关的症状非常相似，疾病行为是对感染的预期生理反应，或者是由于全身IL-1b增加而导致的组织损伤。其次，在CTRS的小鼠模型中，我们已经证明CTR的峰值与全身IL-1的增加有关。第三，以小鼠巨噬细胞为模型系统，我们已经证明了机械上不同的细胞毒性化疗药物可以在3个步骤中刺激IL-1的产生和分泌。第一个信号通过化疗药物的细胞毒作用传递给巨噬细胞，启动这些细胞直接表达前IL-1b，并通过释放内源性Toll样受体激活剂(TLRs)。第二个信号来源于Zak的激活，Zak是化疗药物激活的MAP3K，它延长和加强JNK和p38MAPK的激活，并与核因子-kB协同作用，放大前-IL-1b的表达。化疗药物传递的第三个信号通过诱导NLRP3炎症体复合体的形成，将前-IL-1b转化为其生物活性形式IL-1b。重要的是，IL-1的分泌对化疗药物的反应严重依赖于NLRP3炎症体成分ASC、CASP1和NLRP3。这项为期4年的研究的目的是确定机械上不同的细胞毒性化疗药物是否会触发CTRS，因为它们具有共同的增加IL-1b产生的能力。如果证实，IL-1b信号级联的各个步骤可能为预防或治疗CTRS的干预提供重要的靶点。为了验证我们的假设，我们提出了以下目标：1)确定机械上不同的细胞毒性化疗药物诱导炎性细胞因子的分子机制；2)确定阻断ZAK信号是否降低CTR。3)确定破坏NLRP3炎性小体是否会降低CTR。 公共卫生相关性：接受化疗的患者会出现与治疗相关的症状，如疲倦、不适、食欲下降、睡眠障碍、思考困难、贫血、疼痛、情绪低落以及身体成分的变化。这项建议的目标是阐明这些症状的分子和细胞基础，并测试预防和治疗化疗相关症状的新策略。

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-1¿. Third, using murine macrophages as a model system, we have shown that mechanistically distinct cytotoxic chemotherapeutic agents can stimulate IL-1¿ 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-1¿ 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. PUBLIC HEALTH RELEVANCE: Patients undergoing chemotherapy experience treatment-related symptoms, such as fatigue, malaise, decreased appetite, sleep disturbance, difficulty thinking, anemia, pain, depressed mood, and changes in body composition. The goals of this proposal are to elucidate the molecular and cellular basis of these symptoms and to test novel strategies for prevention and treatment of chemotherapy-related symptoms.