Mechanisms of Symptoms of Multiple Myeloma and Its Therapy

描述(申请人提供)：癌症患者有多种症状，如疼痛、疲劳、睡眠障碍和食欲不振，会导致严重的痛苦、功能和康复，并可能导致治疗延误或过早终止治疗。这些症状是由癌症及其治疗引起的。当癌症是无法治愈的，就像多发性骨髓瘤(MM)一样，积极治疗的副作用和最佳功能之间的平衡变得至关重要。越来越多的证据表明，这些症状中的一些可能聚集在一起，并分享共同的生理机制，创造出一种“症状负担”，即肿瘤负担的主观对应。与正在接受治疗的癌症患者报告的症状惊人地相似的动物“疾病行为”模型的最新进展(Cleeland等人，2003；Lee等人，2004， Dantzer&Kelley，2007)，提供了一个令人兴奋的机会，1)测试症状产生的可能的生理机制，2)检查减少或预防癌症相关症状的新策略。这个项目中要检验的总体假设是，特定的促炎细胞因子，特别是IL-I、IL-6和TNF-a的增加及其前体核因子-kb的激活与单个症状或与治疗相关的症状的出现有关，这些炎症途径的调节将降低症状的患病率和严重程度。为该计划提供的初步数据支持这一假设。 这种性质的项目需要一个基础广泛的综合和多学科项目，其中包括纵向症状评估、免疫学、量化运动和感官评估方面的专业知识，以及可以检查症状表达机制的症状和疾病的动物模型。一个特殊的要求是开发能够解释症状和生物变量随时间变化的关系的统计模型。个别项目的组成部分将跟踪多发性骨髓瘤患者从诊断到诱导治疗、移植和维持治疗。MM提出了一种理想的疾病来检验这些假说，因为促炎细胞因子在疾病的发展中发挥了主要作用，积极的治疗加剧了促炎细胞因子的产生，近年来，关于炎性阻滞剂的知识和可用性的增加，使得机械性症状控制在疾病的发展轨迹中成为一种真正的可能性。 我们的长期目标是为管理疾病和治疗相关症状的机制驱动的症状控制战略奠定基础。通过提高治疗的耐受性和减少治疗后的残留症状，有能力减轻症状负担甚至防止这些后果的治疗将对成千上万的癌症患者和幸存者有潜在的好处。

DESCRIPTION (provided by applicant): Patients with cancer have multiple symptoms, such as pain, fatigue, sleep disturbance, and poor appetite that cause significant distress, impair function and rehabilitation, and may cause treatment delays or premature treatment termination. These symptoms are caused by both the cancer and its therapy. When the cancer is incurable, as is multiple myeloma (MM), the balance between the side effects of aggressive treatment and optimal function becomes critical. There is growing evidence that some of these symptoms may cluster together and share common physiologic mechanisms, creating a "symptom burden" that is the subjective counterpart of tumor burden. The recent evolution of the animal "sickness behavior" model which is strikingly similar to symptoms reported by cancer patients undergoing treatment (Cleeland et al., 2003; Lee et al., 2004, Dantzer & Kelley, 2007), presents an exciting opportunity I) to test for possible physiologic mechanisms of symptom production, and 2) to examine new strategies to reduce or prevent cancer-related symptoms. The overall hypothesis to be tested in this program project is that increases in specific proinflammatory cytokines, especially IL-I, IL-6 and TNF-a, and activation of their precursor, NF-kb, are associated with the emergence of individual symptoms or clusters of treatment-related symptoms, and that modulation of these inflammatory pathways will reduce both the prevalence and severity of symptoms. Preliminary data presented for this program are supportive of this hypothesis. A project of this nature necessitates a broadly based integrated and multidisciplinary Program Project that includes expertise in longitudinal symptom assessment, immunology, quantative motor and sensory assessment, and animal models of symptoms and disease where mechanisms of symptom expression can be examined. A special requirement is for the development of statistical models that can account for the relationship of symptom and biological variables over time. Components of the individual projects will follow MM patients from diagnosis through induction therapy, transplantation, and maintenance therapy. MM presents an ideal disease to test these hypotheses, since proinflammatory cytokines play a major role in the development of the disease, aggressive treatments exacerbate production of proinflammatory cytokines and, in recent years, there has been an increase in knowledge about and availability of agents for inflammatory blockade that make mechanistic symptom control a real possibility in the trajectory of this disease. Our long-term objective is to create a foundation for a mechanism-driven symptom control strategy for managing disease and treatment-related symptoms. Having the ability to reduce symptom burden or even prevent these consequences from therapy would be of potential benefit to thousands of cancer patients and survivors by improving the tolerability of treatment and reducing posttreatment residual symptoms.