Training and Research on Mechanisms of Pancreatic Cancer Associated Muscle Wasting and Related Therapies

胰腺癌相关肌肉萎缩机制及相关治疗的培训和研究

基本信息

批准号：
10299703
负责人：
Calvin Lloyd Cole
金额：
$ 14.27万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-09 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10299703
关键词：
Affect Animals Area Attenuated Autopsy Biological Assay Biological Markers Body Composition CCL2 gene CD80 gene Cancer Patient Cancer Survivor Catabolism Cells Chemotherapy and/or radiation Chronic Development Digestive System Disorders Disease Disease Progression Dose Dual-Energy X-Ray Absorptiometry Enzyme-Linked Immunosorbent Assay Euthanasia Exhibits Fiber Gene Expression Grant Growth Factor Harvest Histology Human Human Pathology Image Immune Implant Infiltration Inflammation Inflammatory Injections Insulin-Like Growth Factor Binding Protein 3 Interleukin-12 Interleukin-6 Intervention Intramuscular Knock-out Laminin Lead Letters Leucocytic infiltrate Lipids Luciferases Malignant Neoplasms Malignant neoplasm of pancreas Malnutrition Measures Microspheres Modeling Molecular Mus Muscle Muscle Fibers Muscular Atrophy Myomatous neoplasm Nebraska Oils Operative Surgical Procedures Outcome Pancreas Pancreatic Ductal Adenocarcinoma Pathologic Pathology Pathway interactions Patients Phenotype Pre-Clinical Model Production Protein Biosynthesis Proteolysis Quantitative Reverse Transcriptase PCR RNA Radiation therapy Randomized Regimen Research Research Personnel Role STAT3 gene Sampling Scientist Serum Signal Transduction Site Skeletal Muscle Solid Neoplasm Stains Syndrome Time Tissue Sample Tissues Toxic effect Training Treatment Failure Treatment Protocols Tumor Burden Tumor-Derived Tumor-infiltrating immune cells Universities Up-Regulation base cancer cachexia cell growth chemokine cohort cytokine density human disease improved in vivo inhibitor/antagonist interstitial lipid biosynthesis macrophage mouse model myogenesis novel pancreatic ductal adenocarcinoma model paracrine prognostic programs quadriceps muscle skeletal muscle wasting subcutaneous transcriptome sequencing tumor growth tumor microenvironment tumor progression

项目摘要

Abstract Skeletal muscle wasting (SMW) is a growing burden among cancer survivors and is prognostic of treatment failure, radiotherapy toxicity, and a shorter time to tumor progression related to survival. This is of particular concern for patients with pancreatic ductal adenocarcinoma (PDAC), for whom interventions for severe SMW are now being implemented prior to surgery, radiation and chemotherapy, so that these patients can complete their prescribe treatments. Currently, the mechanism(s) that lead to cancer-related SMW have yet to be elucidated. Furthermore, viable treatment options for patients with this multifactorial syndrome remain undiscovered. A lack of preclinical models that recapitulate human disease is often identified as an obstacle in the development of feasible therapies to treat cancer-related SMW. To this end, our lab developed a murine model of PDAC-related SMW that parallels human pathology and can be longitudinally assessed via Dual Energy X-ray Absorptiometry (DEXA). In this murine model of PDAC we have identified upregulation of pro-inflammatory cytokines, immune cell infiltration, IGFBP-3, and intramuscular adipogenesis as key features in the progression of SMW. In addition, we determined that a single intratumoral injection of IL-12 reduced tumor burden, pro-inflammatory signaling, and SMW, while improving survival out to 50 days. Although a relationship between chronic low grade inflammation and PDAC-related SMW has been suggested, the mechanisms are unknown. Also, the relationship betwe en macrophage associated increases in IGFBP-3 and adipogenesis have yet to be investigated. Thus, the purpose of this proposal is to investigate a novel pathway of SMW and increased intramuscular adipogenesis via pathologic increases in IGFBP-3 by tumor and immune cells. In addition, we seek to determine the efficacy of a multi-dose IL-12 treatment regimen to ameliorate SMW through the reduction of inflammation, intramuscular macrophage infiltration, IGFBP-3 secretion, and adipogenesis in a murine model of PDAC.

抽象的骨骼肌消耗 (SMW) 是癌症幸存者日益沉重的负担，并且是治疗的预后指标失败、放射治疗毒性以及与生存相关的肿瘤进展时间较短。这是有特殊意义的关注胰腺导管腺癌 (PDAC) 患者，对他们进行严重的干预措施 SMW 现在正在手术、放疗和化疗之前实施，以便这些患者能够完成他们的处方治疗。目前，导致癌症相关 SMW 的机制有：尚待阐明。此外，对于患有这种多因素综合征的患者来说，可行的治疗选择仍未被发现。缺乏概括人类疾病的临床前模型通常被认为是开发治疗癌症相关 SMW 的可行疗法的障碍。为此，我们实验室开发了 PDAC 相关 SMW 的小鼠模型，该模型与人类病理学相似，并且可以纵向通过双能 X 射线吸收测定法 (DEXA) 进行评估。在 PDAC 小鼠模型中，我们发现促炎细胞因子、免疫细胞浸润、IGFBP-3 和肌内注射的上调脂肪生成是 SMW 进展的关键特征。此外，我们确定单个瘤内注射 IL-12 可减少肿瘤负荷、促炎信号传导和 SMW，同时将生存期延长至 50 天。尽管慢性低度炎症与已提出与 PDAC 相关的 SMW，但其机制尚不清楚。另外，之间的关系巨噬细胞相关的 IGFBP-3 增加和脂肪生成仍有待研究。因此，本提案的目的是研究 SMW 和增加肌内注射的新途径通过肿瘤和免疫细胞病理性增加 IGFBP-3 来形成脂肪。此外，我们力求确定多剂量 IL-12 治疗方案通过减少 SMW 来改善 SMW 的功效小鼠炎症、肌内巨噬细胞浸润、IGFBP-3 分泌和脂肪生成的影响 PDAC 模型。