MnBuOE as a Novel Chemosensitizer for Breast Cancer and Neuroprotector

项目摘要 背景：化疗药物治疗后观察到的认知功能障碍是一个重要的 临床问题，对数百万美国人的生活质量的影响迅速增加。一个半 在美国，每年有100万人被诊断患有癌症，超过60%的人存活20年或更长时间。 更多.癌症幸存者长期以来一直报告在疾病过程的各个阶段存在认知功能障碍， 对健康和功能独立性的相关影响。在过去几年中， 过去十年的研究表明，认知障碍早在癌症治疗开始之前就已经发生， 在癌症诊断之前。尽管有认知问题的集体证据，但对肿瘤如何发生知之甚少。 生物学和癌症治疗可以相互作用，导致大脑的变化。本研究将使用 原位小鼠乳腺癌模型，以描述化疗对认知功能的影响。 此外，我们将测试一种新的抗氧化剂是否能够预防化疗/肿瘤的发展， 诱发认知功能障碍 假设：我们假设化疗诱导的氧化应激导致了 神经元结构和线粒体功能损害认知，这将被MnBuOE拯救。 此外，Nrf 2功能对于支持化疗后神经元的维持是至关重要的， 已知ROS产生会加剧。 具体目的1：确定MnBuOE对Nrf 2的药理学上调是否保护大脑免受 化疗引起的损伤。 目的1.1）我们将使用敲除模型来确定Nrf 2是否有助于MnBuOE的保护作用 AC-T引起的脑损伤 目的1.2）确定受损的Nrf 2表达是否在化疗的发病机制中起关键作用- 导致脑损伤。 具体目标2：描述由以下原因引起的行为、神经解剖学和形态学变化 化疗和MnBuOE在同基因模型中的补救作用。 目的2.1）表征与肿瘤相关的脑中线粒体生物能量变化± 化疗和MnBuOE治疗的效果。 具体目标3：评估MnBuOE对肿瘤生长和化疗敏感性的影响（AC-T） 在患者来源的荷瘤动物模型中

Project Summary Background: The cognitive deficits observed after treatment with chemotherapeutic drugs are a significant clinical problem, with a rapidly increasing impact on the quality of life of millions of Americans. One and a half million people are diagnosed with cancer every year in the US, and more than 60% survive for 20 years or more. Cancer survivors have long reported cognitive dysfunction at various stages of the disease course with associated consequences upon well-being and functional independence. Several studies conducted over the past decade have indicated that cognitive impairment occurs long before cancer treatment begins and even before cancer diagnosis. Despite collective evidence for cognitive problems, far less is known about how tumor biology and cancer treatments can interact to lead to changes in the brain. The present study will use an orthotopic mouse model of breast cancer to delineate the effects chemotherapy on cognitive function. Moreover, we will test whether a novel antioxidant is capable of preventing the development of chemo/tumor- induced cognitive dysfunction. Hypothesis: We hypothesize that oxidative stress induced by chemotherapy treatment leads to changes in neuronal architecture and mitochondrial function impairing cognition which will be rescued by MnBuOE. Furthermore, Nrf2 function is critical for supporting neuronal maintenance after chemotherapy when aberrant ROS production is known to be exacerbated. Specific Aim 1: Determine if pharmacological upregulation of Nrf2 by MnBuOE protects the brain from chemotherapy induced injury. Aim 1.1) We will use a knockout model to determine if Nrf2 contributes to the protective effect of MnBuOE toward AC-T-induced brain injury. Aim 1.2) Determine if impaired Nrf2 expression plays a critical role in the pathogenesis of chemotherapy- induced brain injury. Specific Aim 2: Characterize the behavioral, neuroanatomical and morphological changes due to chemotherapy and the remediating effects of MnBuOE in a syngeneic model. Aim 2.1) Characterize mitochondrial bioenergetic changes in the brain associated with tumor ± chemotherapy and the effects of MnBuOE treatment. Specific Aim 3: Assess the influence of MnBuOE on tumor growth and susceptibility to chemotherapy (AC-T) in a patient derived tumor bearing animal model