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

描述（由申请方提供）：本R21提案旨在研究Meriva（一种具有增强吸收特性的营养保健品姜黄素的独特制剂）在减少接受乳腺癌治疗的女性循环外周血单核细胞（PBMC）中核因子-κ B（NF-κ B）通路的化疗和放疗（XRT）相关活化方面的疗效。据了解，多达60%接受放射治疗的乳腺癌患者会出现疲劳，约30%的患者在治疗完成后数月至数年内持续疲劳。因此，疲劳是一个持续存在的问题，即使在成功完成乳腺癌治疗后也是如此。患者产生疲劳的生理，心理和分子机制知之甚少，很可能是多因素的。然而，一种受到相当大关注的途径是核因子-κ B（NF-kB）。我们的工作表明，循环免疫细胞中的NF-kB通路活性与接受放射治疗的患者的疲劳发展相关。重要的是，我们还发现，持续性疲劳和NF-κ B通路活性的风险最大的患者是那些因乳腺癌接受化疗和放疗的患者。因此，我们认为NF-kB是治疗乳腺癌相关疲劳的重要靶点。姜黄素是姜黄的主要成分，来源于植物姜黄素，已被证明会影响许多分子信号传导途径，包括NF-κ B。尽管姜黄素作为食品添加剂已有几个世纪，并且作为营养药被广泛食用，但口服姜黄素调节NF-κ B的有效性被认为受到姜黄素吸收不良的严重限制。Meriva是一种姜黄素制剂，包括磷脂酰胆碱。与单独的姜黄素相比，磷脂酰胆碱与姜黄素的组合已显示出增强姜黄素的吸收。因此，Meriva代表了一种令人兴奋的方式，可以减少接受化疗和放疗的乳腺癌妇女的NF-kB激活和疲劳。到目前为止，Meriva已经在几种疾病的背景下显示出相当大的希望，包括2型糖尿病，骨关节炎和慢性前葡萄膜炎。然而，Meriva预防和逆转乳腺癌患者疲劳的有效性尚待评估。本提案旨在解决这一问题。值得注意的是，我们在Emory的团队成员已经收到了FDA针对拟议研究的IND。目前建议的主要假设是，Meriva将减少在NF-kB水平测量的炎症激活以及下游促炎细胞因子治疗乳腺癌的妇女。我们还预测Meriva将以与减少炎症相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.