Meriva for treatment-induced inflammation and fatigue in women with breast cancer

描述(申请人提供)：这项R21提案旨在研究Meriva的疗效，Meriva是一种独特的中性姜黄素配方，具有增强的吸收特性，可减少乳腺癌治疗女性患者循环外周血单个核细胞(PBMC)中因化疗和放疗(XRT)而导致的核因子-kB(NF-kB)途径的激活。已知，接受放射治疗的乳腺癌患者中有60%会出现疲劳，其中约30%的患者在治疗完成后几个月至几年内会出现持续性疲劳。因此，疲劳是一个持续存在的问题，即使在成功完成乳腺癌的治疗后也是如此。患者产生疲劳的生理、心理和分子机制还知之甚少，很可能是多因素的。然而，核因子-kB(NF-kB)是其中一个备受关注的途径。我们的工作表明，循环免疫细胞中的核因子-kB途径活性与放射治疗患者的疲劳发展有关。重要的是，我们还发现，那些因乳腺癌同时接受化疗和放疗的患者，存在持续性疲劳和核因子-kB途径活性的风险最大的患者。因此，我们认为，核因子-kB是治疗乳腺癌相关性疲劳的一个重要靶点。姜黄素是姜黄的主要成分，从植物姜黄素中提取，已被证明影响包括核因子-kB在内的许多分子信号通路。尽管姜黄素几个世纪以来一直是一种食品添加剂，并被广泛用作中性食品，但口服姜黄素调节核因子-kB的有效性被认为受到吸收不良或姜黄素的严重限制。Meriva是一种含有磷脂酰胆碱的姜黄素制剂。与单独使用姜黄素相比，磷脂酰胆碱与姜黄素联合使用可增强姜黄素的吸收。因此，Meriva代表了一种令人兴奋的方法，通过这种方法可以减少接受乳腺癌化疗和放射治疗的妇女的核因子-kB激活和疲劳。到目前为止，Meriva在包括2型糖尿病、骨关节炎和慢性前葡萄膜炎在内的几种疾病方面表现出了相当大的希望。然而，在乳腺癌的情况下，Meriva预防和扭转疲劳的有效性还有待评估。这项提议就是为了解决这个问题。值得注意的是，我们在埃默里的团队成员已经收到了FDA对拟议研究的IND。目前这项提议的主要假设是，Meriva将减少在接受乳腺癌治疗的妇女中以核因子-kB水平测量的炎症激活以及下游的促炎细胞因子。我们还预测，Meriva将以一种与减少炎症有关的方式减少疲劳症状。除了证明Meriva对乳腺癌治疗后的女性疲劳有积极影响外，这里提出的研究还将建立姜黄素对疲劳的作用机制。

DESCRIPTION (provided by applicant): This R21 proposal is designed to investigate the efficacy of Meriva, a unique formulation of the neutraceutical curcumin with enhanced absorption properties, to reduce chemotherapy and radiotherapy (XRT)-associated activation of the nuclear factor-kappa B (NF-kB) pathway in circulating peripheral blood mononuclear cells (PBMCs) in women treated for breast cancer. As many as 60% of breast cancer patients who receive radiation are known to develop fatigue, with about 30% suffering persistent fatigue several months to years after treatment completion. Fatigue therefore represents a persistent problem, even after successful completion of treatment for breast cancer. The physical, psychological, and molecular mechanisms by which patients develop fatigue are poorly understood and are most likely multi-factorial. However, one pathway that has received considerable attention is nuclear factor-kappa B (NF-kB). Our work has shown that NF-kB pathway activity in circulating immune cells is associated with the development of fatigue in patients treated with radiation. Importantly, we have also found that patients most at risk for persistent fatigue and NF-kB pathway activity are those who have received both chemotherapy and radiation for their breast cancer. We therefore believe that NF-kB represents an important target for the treatment of breast cancer-related fatigue. Curcumin, the principal component of turmeric and derived from the plant curcumin longa, has been shown to impact a number of molecular signaling pathways, including NF-kB. Although curcumin has been a food additive for centuries and is widely consumed as a neutraceutical, the effectiveness of orally administered curcumin to modulate NF-kB is believed to be severely limited by the poor absorption or curcumin. Meriva is a curcumin formulation that includes phosphatidylcholine. The combination of phosphatidylcholine with curcumin has been shown to enhance the absorption of curcumin compared to curcumin alone. As a result, Meriva represents an exciting way by which to reduce NF-kB activation and fatigue in women treated with chemotherapy and radiation for breast cancer. To date Meriva has shown considerable promise in the context of several disorders, including type-2 diabetes, osteoarthritis and chronic anterior uveitis. However, the effectiveness of Meriva to prevent and reverse fatigue in the context of breast cancer is yet to be evaluated. This proposal is designed to address this. Of note, our team members at Emory have already received an IND from FDA for the studies proposed. The major hypothesis of the current proposal is that Meriva will reduce inflammatory activation measured at the level of NF-kB as well as downstream proinflammatory cytokines in women treated for breast cancer. We also predict that Meriva will decrease fatigue symptoms, in a manner that is associated with reduced inflammation. Besides demonstrating that Meriva positively affects fatigue in women after breast cancer treatment, studies proposed here will also establish a mechanism for action for curcumin on fatigue.