DEVELOPMENT OF TARGETED APPROACHES IN PREVENTION OF CANCER-CACHEXIA

项目摘要 癌症恶病质（CC），肌肉质量的损失，不能通过营养干预完全逆转， 相对于其他肌肉病变，研究不足，影响高达80%的患者，并负责20-40% 与癌症有关的死亡。不幸的是，预防CC的治疗方法缺乏疗效。我们最近 证明了肌肉代谢健康，特别是线粒体网络的退化和功能障碍， 在刘易斯肺癌诱导的（LLC）CC中，在肌肉损失之前就已经受损。具体来说，我们观察到 线粒体活性氧（ROS）释放增加，Opa 1蛋白降低， 肿瘤植入物，随后在2周时线粒体网络变性，呼吸功能受损 功能和诱导线粒体自噬蛋白BNIP 3在3周与肌肉损失4周。我们的初步证据 表明通过针对线粒体质量（例如，Opa 1激活，BNIP-3， 线粒体抗氧化剂）。这些数据提供了新的见解，潜在的机制，可能是针对 预防CC的发生，并强调预防措施的必要性。我们实验室的首要目标 该建议是利用CC发展过程中关键步骤的特征来识别机制， 有效的治疗方法。然而，许多问题仍然存在：1）这种事态发展是否会持续下去 不同类型的恶病质2)荷瘤状态如何与CC的化疗相互作用？3)我们能 专门针对前浪费的影响，以防止CC？4)我们能否将药物特异性地输送到肌肉中， CC？为了回答这些问题，我们将追求以下目标（图1）： 目标1.在其他临床前模型中定义癌症诱导的肌肉萎缩的发展， 与化疗结合。 目标2.确定在CC发展中识别的节点是否可以作为预防或减弱肌肉的目标 浪费 目标3.确定是否有针对性的或肌肉特异性的治疗药物可以预防CC。

PROJECT SUMMARY Cancer-cachexia (CC), loss in muscle mass that cannot be fully reversed through nutritional intervention, is understudied relative to other muscle pathologies, affects up to 80% of patients and is responsible for 20-40% of cancer-related deaths. Unfortunately, therapeutic approaches to prevent CC lack efficacy. We recently demonstrated muscle metabolic health, specifically degeneration and dysfunction of the mitochondrial network, is compromised well before muscle loss in Lewis Lung Carcinoma-induced (LLC) CC. Specifically, we observed enhanced mitochondrial reactive oxygen species (ROS) emission and depressed Opa1 protein 1 wk following tumor implant with subsequent degeneration of the mitochondrial network at 2 wks, and impaired respiratory function and induction of mitophagy protein BNIP3 at 3 wks with muscle loss at 4 wks. Our preliminary evidence suggests attenuation of CC is possible by targeting mitochondrial quality (e.g., Opa1 activation, BNIP-3, mitochondrial antioxidants). These data provide novel insight to potential mechanisms that may be targeted to prevent onset of CC and highlight the need for preventive measures. The overarching goal of our laboratory and this proposal is to utilize characterization of key steps in development of CC to identify mechanisms and efficacious therapeutic approaches. However, many questions remain: 1) Does this course of events persist across models of cachexia? 2) How does the tumor-bearing state interact with chemotherapy on CC? 3) Can we specifically target pre-wasting effects to prevent CC? 4) Can we specifically deliver drugs to muscle to prevent CC? To answer these questions, we will pursue the following aims (Fig 1): Aim 1. Define development of cancer-induced muscle wasting across additional pre-clinical models and in conjunction with chemotherapy. Aim 2. Determine if nodal points identified in development of CC may be targeted to prevent or attenuate muscle wasting. Aim 3. Determine if mitochondria-targeted or muscle-specific delivery of therapeutics prevents CC.