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.

项目总结/文摘

项目成果

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

• DOI: 10.1002/ctm2.1391
• 发表时间: 2023-10
• 期刊: CLINICAL AND TRANSLATIONAL MEDICINE
• 影响因子: 10.6
• 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, Nasser K.;Goncalves, Marcus D.
• 通讯作者: Goncalves, Marcus D.

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

• DOI: 10.1002/crt2.15
• 发表时间: 2020
• 期刊: JCSM clinical reports
• 作者: J. Vitarello;M. Goncalves;Qin C Zhou;A. Iasonos;D. Halpenny;A. Plodkowski;E. Schwitzer;Jennifer J Mueller;O. Zivanovic;L. Jones;K. Cadoo;J. Konner
• 通讯作者: J. Konner

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。

• DOI: 10.1101/2023.07.31.551241
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Langer,HenningTim;Ramsamooj,Shakti;Dantas,Ezequiel;Murthy,Anirudh;Ahmed,Mujmmail;Hwang,Seo-Kyoung;Grover,Rahul;Pozovskiy,Rita;Liang,RogerJ;Queiroz,AndreLima;Brown,JustinC;White,EileenP;Janowitz,Tobias;Goncalves,AndMarcusD
• 通讯作者: Goncalves,AndMarcusD

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

• DOI: 10.1177/15347354211032283
• 发表时间: 2021-01
• 期刊: Integrative cancer therapies
• 影响因子: 2.9
• 作者: Blow T;Hyde PN;Falcone JN;Neinstein A;Vasan N;Chitkara R;Hurd MA;Sardesai S;Lustberg MB;Flory JH;Volek JS;Goncalves MD
• 通讯作者: Goncalves MD

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

• DOI: 10.3389/fonc.2022.903157
• 发表时间: 2022
• 期刊: FRONTIERS IN ONCOLOGY
• 影响因子: 4.7
• 作者: Langer, Henning Tim;Ramsamooj, Shakti;Liang, Roger J.;Grover, Rahul;Hwang, Seo-Kyoung;Goncalves, Marcus DaSilva
• 通讯作者: Goncalves, Marcus DaSilva