DEVELOPMENT OF TARGETED APPROACHES IN PREVENTION OF CANCER-CACHEXIA

项目总结 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，是 相对于其他肌肉病理研究不足，影响高达80%的患者，并对20%-40%的患者负责 与癌症相关的死亡人数。不幸的是，预防CC的治疗方法缺乏疗效。我们最近 显示肌肉代谢健康，特别是线粒体网络的退化和功能障碍， 在Lewis肺癌诱导(LLC)CC中，在肌肉丧失之前就已经受到损害。具体来说，我们观察到 1wk后线粒体ROS释放增加和OPA1蛋白降低 肿瘤植入后2周线粒体网络变性，呼吸受损 3周时吞丝分裂蛋白BNIP3的功能和诱导，4周时肌肉丢失。我们的初步证据 提示可以通过靶向线粒体质量(例如OPA1激活，BNIP-3， 线粒体抗氧化剂)。这些数据为潜在的机制提供了新的见解，这些机制可能是 预防CC的发病，并强调预防措施的必要性。我们实验室的首要目标是 这项提议是利用对发展CC的关键步骤的表征来确定机制和 有效的治疗方法。然而，许多问题仍然存在：1)这种情况是否会持续下去 跨恶病质模型？2)荷瘤状态如何与CC的化疗相互作用？3)我们能 专门针对预消耗效应以防止CC？4)我们是否可以专门将药物输送到肌肉以防止 抄送？为了回答这些问题，我们将追求以下目标(图1)： 目的1：通过其他临床前模型和临床试验，确定癌症引起的肌肉萎缩的发展。 配合化疗。 目的2.确定在CC发展过程中发现的结点是否可以作为预防或减弱肌肉的靶点 浪费。 目的3.确定线粒体靶向或肌肉特异性给药是否可预防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.