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

摘要 骨骼肌萎缩(SMW)是癌症幸存者日益加重的负担，也是治疗的预后 失败、放疗毒性和较短的肿瘤进展时间与生存有关。这是特别的 关注胰腺导管腺癌(PDAC)患者，对其进行重症干预 SMW现在在手术、放疗和化疗之前实施，这样这些患者就可以 完成他们的处方治疗。目前，导致癌症相关SMW的机制(S)有 目前尚不清楚。此外，对于这种多因素综合征患者，可行的治疗方案 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一种 在开发治疗癌症相关SMW的可行疗法方面存在障碍。为此，我们的实验室 建立了一种与人类病理相似的与PDAC相关的SMW小鼠模型，该模型可以纵向 通过双能X线骨密度仪(DEXA)进行评估。在这个PDAC的小鼠模型中，我们已经发现 促炎症细胞因子、免疫细胞浸润、IGFBP-3和肌内表达上调 脂肪生成是SMW进展的关键特征。此外，我们确定了一个单一的 瘤内注射IL-12可降低肿瘤负荷、促炎信号和SMW，而 将存活期提高到50天。尽管慢性低度炎症与 PDAC相关的SMW已被提出，但其机制尚不清楚。另外，我们之间的关系 巨噬细胞相关的IGFBP-3的增加和脂肪形成还没有被研究。因此， 这项建议的目的是研究一种新的SMW和肌内增加的途径 通过病理性增加肿瘤和免疫细胞中IGFBP-3的表达来促进脂肪生成。此外，我们寻求 确定多剂量IL-12治疗方案通过减少体重改善SMW的疗效 炎症、肌内巨噬细胞浸润、IGFBP-3分泌与小鼠脂肪形成的关系 PDAC的模型。

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.