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

• 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
• 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

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 骨骼肌浪费（SMW）是癌症幸存者的越来越负担，并且是治疗的预后 衰竭，放射疗法毒性以及与生存有关的肿瘤进展时间较短。这是特别的 关注胰腺导管腺癌（PDAC）的患者，为严重的干预措施 现在正在进行手术，放射和化学疗法之前实施SMW，以便这些患者可以 完成他们的处方治疗。目前，导致与癌症相关的SMW的机制具有 尚待阐明。此外，该多因素综合征患者的可行治疗选择 保持未被发现。缺乏概括人类疾病的临床前模型通常被确定为 可行治疗与癌症相关的SMW的可行疗法的障碍。为此，我们的实验室 开发了与PDAC相关的SMW的鼠模型，该模型与人类病理平行，可以纵向 通过双能X射线吸收法（DEXA）评估。在这个PDAC的鼠模型中，我们已经确定了 促炎细胞因子，免疫细胞浸润，IGFBP-3和肌肉内的上调 脂肪形成是SMW进展的关键特征。此外，我们确定一个 肿瘤内注射IL-12减轻了肿瘤负担，促炎信号和SMW，而SMW则 将生存提高到50天。虽然慢性低年级炎症与 已经提出了与PDAC相关的SMW，这些机制尚不清楚。另外，恋爱关系 巨噬细胞与IGFBP-3和脂肪形成的相关增加尚未研究。因此， 该建议的目的是研究SMW的新途径和肌肉内增加的途径 通过肿瘤和免疫细胞在IGFBP-3中通过病理学增加的脂肪形成增加。此外，我们试图 确定多剂量IL-12处理方案通过还原改善SMW的功效 炎症，肌内巨噬细胞浸润，IGFBP-3分泌和脂肪形成 PDAC的模型。