The Role of Hypoketonemia in the Cancer Anorexia-Cachexia Syndrome

低酮血症在癌症厌食恶病质综合征中的作用

• 批准号: 10222611
• 负责人: Marcus DaSilva Goncalves
• 金额: $ 14.97万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-05-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10222611
• 关键词: Adipose tissue; Adrenal Glands; Advisory Committees; Agonist; Amino Acids; Animal Model; Automobile Driving; Biochemistry; Body Weight; Butylene Glycols; Cachexia; Cancer Biology; Catabolism; Cells; Chemicals; Clinical; Core Facility; Data; Development; Diagnosis; Diet; Dietary Intervention; Doctor of Philosophy; Endocrinology; Environment; Etiology; Fenofibrate; Future; Genetic; Genetically Engineered Mouse; Glucocorticoid Receptor; Glucocorticoids; Gluconeogenesis; Hepatic; High Prevalence; Human; Ketones; Knock-out; Liver; Mediator of activation protein; Medical center; Mentorship; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Mifepristone; Modeling; Monitor; Mus; Muscle; Muscular Atrophy; Non-Small-Cell Lung Carcinoma; Nutrient; Outcome; PPAR alpha; Pathway interactions; Patients; Physicians; Production; Proteins; Proteomics; Quality of life; Replacement Therapy; Reporter; Research; Research Personnel; Resources; Role; Scientist; Serum; Signal Transduction; Skeletal Muscle; Syndrome; System; Talents; Testing; Therapeutic; Time; Tissues; Toxin; Training; Training Programs; Tumor-Derived; Tumor-Secreted Protein; advanced disease; base; cancer anorexia; cancer therapy; career; career development; differential expression; effective therapy; expectation; experimental study; hypothalamic-pituitary-adrenal axis; in vivo; inhibitor/antagonist; ketogenic diet; liver metabolism; metabolic profile; mortality; muscle form; muscle metabolism; new therapeutic target; novel; preclinical efficacy; prevent; programs; release factor; skeletal muscle wasting; skills; success; transcriptome sequencing; tumor

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.

项目概要/摘要 该提案描述了一个为期五年的培训计划，旨在在小众小说中开展研究生涯 内分泌学和癌症生物学的交叉点 该候选人是威尔康奈尔大学的内分泌学研究员。 医疗中心，十多年来一直接受成为一名医师科学家的培训。 研究将在癌症生物学领域的领导者 Lewis C. Cantley 博士的指导下进行 和生物化学，培养了许多年轻的研究人员 一个由才华横溢的科学家组成的咨询委员会。 该研究还旨在为职业发展和实验提供指导。 环境提供了广泛的资源、核心设施和智力专长，因此是理想的。 培养成为独立医师科学家所需技能的培训环境。 教学课程和专业发展研讨会将提高该计划的教育成功率。 癌症厌食-恶病质综合征（CACS）是一种全身代谢性疾病，其特征是 CACS 患者的肌肉和脂肪组织等营养丰富的组织的分解代谢有所减少。 限制肌肉损失的治疗策略是限制活动能力、生活质量恶化和生存期缩短。 预计可以扭转这些有害结果，但独立于直接癌症治疗之外，CACS 还没有有效的方法。 治疗或已知病因部分是因为动物模型很难模拟患者的研究结果。 使用非小细胞肺癌诱导型基因工程小鼠模型进行初步实验 (NSCLC)，申请人已经鉴定并表征了一种能够在人类中可靠复制 CACS 的模型。 小鼠表现出独特的代谢特征，其特征是 PPARα 依赖性酮产生的丧失 使用 PPARα 激动剂恢复酮的产生， 非诺贝特可减少糖皮质激素并防止骨骼肌质量和体重的损失。 该提案扩展了初步实验，并试图澄清之间的因果关系 观察到 NSCLC 相关 CACS 中全身代谢和骨骼肌损失的变化。 提出的目的是检验骨骼肌退化是由于酮的损失而导致的假设 此外，该提案将寻求减少糖皮质激素的生产（目标 1）或随后的增加（目标 2）。 鉴定启动 CACS 小鼠肝 PPARα 表达减少的肿瘤释放因子（目的 3).这些实验将阐明在动物模型中驱动肌肉损失的全身代谢信号。 准确模拟观察到的临床综合征的非小细胞肺癌（NSCLC）的期望是识别特定的肿瘤。 分泌的蛋白质可减少肝酮的产生，并证明酮替代疗法是一种 这些结果不仅将进一步加深我们对 CACS 启动的理解，而且还将促进我们的研究。 强调未来治疗基础的新途径。

项目成果

Restoring adiponectin via rosiglitazone ameliorates tissue wasting in mice with lung cancer.

通过罗格列酮恢复脂联素可改善肺癌小鼠的组织消耗。

• 发表时间: 2023-08-02
• 作者: Langer, Henning Tim;Ramsamooj, Shakti;Dantas, Ezequiel;Murthy, Anirudh;Ahmed, Mujmmail;Hwang, Seo;Grover, Rahul;Pozovskiy, Rita;Liang, Roger J;Queiroz, Andre Lima;Brown, Justin C;White, Eileen P;Janowitz, Tobias;Goncalves, And Marcus D
• 通讯作者: Goncalves, And Marcus D

Systemic Ketone Replacement Does Not Improve Survival or Cancer Cachexia in Mice With Lung Cancer.

全身酮替代不能改善肺癌小鼠的生存或癌症恶病质。

• 发表时间: 2022
• 作者: Langer, Henning Tim;Ramsamooj, Shakti;Liang, Roger J;Grover, Rahul;Hwang, Seo;Goncalves, Marcus DaSilva
• 通讯作者: Goncalves, Marcus DaSilva

The effects of neoadjuvant chemotherapy and interval debulking surgery on body composition in patients with ovarian cancer.

新辅助化疗和间隔减瘤手术对卵巢癌患者身体成分的影响。

• 发表时间: 2021-01
• 作者: Vitarello, John;Goncalves, Marcus D;Zhou, Qin C;Iasonos, Alexia;Halpenny, Darragh F;Plodkowski, Andrew;Schwitzer, Emily;Mueller, Jennifer J;Zivanovic, Oliver;Jones, Lee W;Cadoo, Karen A;Konner, Jason A
• 通讯作者: Konner, Jason A

Treating Alpelisib-Induced Hyperglycemia with Very Low Carbohydrate Diets and Sodium-Glucose Co-Transporter 2 Inhibitors: A Case Series.

用极低碳水化合物饮食和钠-葡萄糖协同转运蛋白 2 抑制剂治疗 Alpelisib 引起的高血糖：案例系列。

• 发表时间: 2021-01
• 影响因子: 2.9
• 作者: Blow, Tahj;Hyde, Parker N;Falcone, John N;Neinstein, Aaron;Vasan, Neil;Chitkara, Ritika;Hurd, Maurice A;Sardesai, Sagar;Lustberg, Maryam B;Flory, James H;Volek, Jeff S;Goncalves, Marcus D
• 通讯作者: Goncalves, Marcus D

TIMP1 is an early biomarker for detection and prognosis of lung cancer.

TIMP1是肺癌检测和预后的早期生物标志物。

• 发表时间: 2023-10
• 作者: Dantas, Ezequiel;Murthy, Anirudh;Ahmed, Tanvir;Ahmed, Mujmmail;Ramsamooj, Shakti;Hurd, Maurice A;Lam, Tiffany;Malbari, Murtaza;Agrusa, Christopher;Elemento, Olivier;Zhang, Chen;Pappin, Darryl J;McGraw, Timothy E;Stiles, Brendon M;Altorki, Na
• 通讯作者: Altorki, Na