The Role of Hypoketonemia in the Cancer Anorexia-Cachexia Syndrome

项目总结/摘要 该提案描述了一个为期五年的培训计划，以启动在一个新的利基研究职业生涯， 内分泌学和癌症生物学的交叉点。候选人是威尔康奈尔大学的内分泌学研究员 医学中心，谁一直在训练成为一个医生，科学家超过十年。拟议 研究将在刘易斯C. Cantley博士，癌症生物学领域的领导者 他培养了许多年轻的研究人员。由天才科学家组成的顾问委员会 也被集合起来，提供职业发展和实验方面的指导。研究 环境提供了广泛的资源，核心设施和知识专长。因此，这是一种理想 培训环境，其中发展必要的技能，成为一个独立的医生，科学家。参与 在教学课程和专业发展研讨会将提高该计划的教育成功。 癌症恶病质综合征（CACS）是一种全身性代谢紊乱，其特征是 营养丰富的组织，如肌肉和脂肪组织的分解。CACS患者减少 流动性，生活质量下降，生存期缩短。限制肌肉损失的治疗策略是 预测可以逆转这些有害的结果，独立于直接的癌症治疗。CACS没有有效的 这在一定程度上是因为动物模型不能很好地模拟患者的发现。但在 使用可诱导的非小细胞肺癌基因工程小鼠模型的初步实验 （NSCLC），申请人已经鉴定并表征了在人体中可靠复制CACS的模型。这些 小鼠表现出独特的代谢特征，其特征在于通过以下途径丧失了PPARα依赖性酮的产生： 肝脏和内源性糖皮质激素水平升高。使用PPARα激动剂恢复酮的产生， 非诺贝特，减少糖皮质激素和防止骨骼肌质量和体重的损失。 这一建议扩大了初步实验，并试图澄清因果关系， 在NSCLC相关CACS中观察到的全身代谢和骨骼肌损失的变化。的 提出的目的是检验骨骼肌降解是由于酮的损失的假设 生产（目标1）或随后的糖皮质激素（目标2）的增加。此外，该提案将寻求 确定启动CACS小鼠肝脏PPARα表达降低的肿瘤释放因子（目的 3）。这些实验将阐明全身代谢信号驱动肌肉损失的动物模型， 准确模拟观察到的临床综合征的NSCLC。希望能找出特定的肿瘤- 分泌的蛋白质，减少肝酮的产生，并证明酮替代疗法是一种有效的治疗方法。 有用的治疗策略。这些结果不仅将进一步加深我们对CACS启动的理解， 突出了未来治疗基础新途径。

Project Summary/Abstract This proposal describes a five-year training program to launch a research career in a novel niche at the intersection between endocrinology and cancer biology. The candidate is an endocrinology fellow at Weill Cornell Medical Center, who has been training to become a physician-scientist for over ten years. The proposed research will be carried out under the mentorship of Lewis C. Cantley, PhD, a leader in the field of cancer biology and biochemistry who has trained numerous young investigators. An advisory committee of talented scientists has also been assembled to offer guidance in career development and experimentation. The research environment provides extensive resources, core facilities, and intellectual expertise. Therefore, it is an ideal training setting in which to develop the requisite skills to become an independent physician-scientist. Participation in didactic courses and professional development seminars will enhance the educational success of the program. The cancer anorexia-cachexia syndrome (CACS) is a systemic metabolic disorder characterized by the catabolism of nutrient-rich tissues, such as muscle and adipose tissue. Patients with CACS have reduced mobility, worsened quality of life, and shortened survival. Therapeutic strategies to limit muscle loss are predicted to reverse these deleterious outcomes, independent of direct cancer treatment. CACS has no effective treatment or known etiology, in part, because animal models poorly mimic the findings in patients. However, in preliminary experiments using an inducible, genetically engineered mouse model of non-small cell lung cancer (NSCLC), the applicant has identified and characterized a model that reliably replicates CACS in humans. These mice display a unique metabolic profile, characterized by the loss of PPARα-dependent ketone production by the liver and a rise in endogenous glucocorticoid levels. Restoring ketone production using the PPARα agonist, fenofibrate, reduces glucocorticoids and prevents the loss of skeletal muscle mass and body weight. This proposal expands upon the preliminary experiments and seeks to clarify the causal relationship between the observed changes in systemic metabolism and skeletal muscle loss in NSCLC-associated CACS. The proposed aims are to test the hypothesis that skeletal muscle degradation results from the loss of ketone production (Aim 1) or the subsequent rise in glucocorticoids (Aim 2). Additionally, this proposal will seek to identify the tumor-released factor that initiates the reduction in hepatic PPARα expression in CACS mice (Aim 3). These experiments will elucidate the systemic metabolic signals driving muscle loss in an animal model of NSCLC that accurately mimics the observed clinical syndrome. The expectations are to identify specific tumor- secreted proteins that reduce hepatic ketone production, and demonstrate that ketone replacement therapy is a useful therapeutic strategy. These results will not only further our understanding of CACS initiation, but will also highlight novel pathways on which to base future therapy.