Pancreatic adenocarcinoma secretome as a dynamic biomarker for patient stromal reprogramming efficacy

项目概要/摘要 据预测，胰腺癌很快将成为美国癌症死亡的第二大原因。为 早期诊断的患者很少，手术是最好的选择，但单纯手术很少能治愈。因此，术前 化疗加放疗有可能增加长期生存的可能性。一个独特 胰腺癌的标志是“结缔组织增生”;胰腺癌的非肿瘤细胞扩张和纤维化。癌 小区修改局部邻域小区（即，结缔组织增生或间质），而不是 通常通过特定的癌症相关成纤维细胞（CAF）限制肿瘤生长。Fox Chase Cancer附近酒店 Marvin & Concetta Greenberg胰腺癌研究所中心，大量的前期工作已经建立了关键 胰腺邻近区域、肿瘤产生的局部纤维化和患者存活率之间的关系。 当邻近细胞（包括CAF、免疫细胞和其他细胞）被上皮细胞和/或细胞因子改变时， 术前治疗时，这种局部反应可能引起治疗抵抗。理解这种关系是关键 在治疗胰腺癌中，有效的治疗必须针对邻近细胞的“正常化”， 恢复其天然的肿瘤抑制活性。人们对各种旁分泌的影响知之甚少， 作为上皮肿瘤细胞、CAF、免疫细胞和其他成分之间语言的介质 肿瘤。此外，对于我们理解哪些趋化因子和细胞因子是 胰腺癌新辅助治疗的影响。 在这项研究中，我们将确定肿瘤附近的分泌体信号球员的变化， 进行术前治疗本研究旨在验证监测分泌变化的可行性 在化疗/放疗后和手术前实施新的治疗干预后， 重新编程基质及其相互作用。 我们将利用手术前4-6周的等待期，作为“机会之窗”， 三种微环境“正常化”药物（PHL：帕立骨化醇、羟氯喹和氯沙坦）， 在接受化疗的胰腺癌患者中，每种药物均表现出极好的耐受性。在这个阶段 在一项试验中，我们将确定量化总新辅助治疗/PHL组合的效果的可行性。 通过胰腺中的炎性和增殖性趋化因子和细胞因子测量， 汁.建立一个“机会之窗”抽样的范例将使我们能够评估我们的影响能力 在分泌组水平上的“邻域正常化”假设。最终，这项研究将作为一个模型， 实时治疗和监测后续患者的疗效，并测试新的有前途的治疗方法， 未来胰腺癌“机会之窗”试验。

PROJECT SUMMARY/ABSTRACT Pancreatic cancer is predicted to soon become the second leading cause of cancer deaths in the USA. For the few patients diagnosed early, surgery is the best option, yet surgery alone is rarely curative. Hence, preoperative chemotherapy plus radiotherapy have a potential of increasing the possibility for long-term survival. A unique hallmark of pancreatic cancer is “desmoplasia”; pancreatic cancer’s non-tumor cells expansion & fibrosis. Cancer cells modify the local neighborhood cells (i.e., desmoplasia or stroma) in a way that these promote, instead of normally restrict, tumor growth via specific cancer associated fibroblastic cells (CAFs). At the Fox Chase Cancer Center Marvin & Concetta Greenberg Pancreatic Cancer Institute, extensive prior work has established the key relationship between the pancreatic neighborhood, the neoadjuvant-generated local fibrosis, & patient survival. When the neighborhood cells (including CAFs, immune & other cells) are altered by the epithelial cells and/or by preoperative therapy, this local reaction may engage therapy resistance. Understanding this relationship is key in treating pancreatic cancer & effective therapy must be aimed at “normalization” of the neighborhood cells to return its natural tumor suppressive activity. What is poorly understood is the impact of the various paracrine mediators that act as the language between epithelial tumor cells, CAFs, immune cells, and other constituents of the tumor. Further, a gap in our knowledge exists for our understanding of which chemokines & cytokines are influenced by neoadjuvant therapy in pancreatic cancer. In this study we will determine the changes in tumor-neighborhood secretome signaling players associated with preoperative therapy. The study proposes to test the feasibility of monitoring the secretory changes subsequent to a new therapy intervention, implemented after chemo/radiation & before surgery, aimed to reprogram the stroma and its interactions. We will take advantage of the 4-6 week waiting period before surgery, as a “Window of Opportunity,” to test three microenvironment “normalizing” drugs (PHL: paricalcitol, hydroxychloroquine, & losartan) with demonstrated excellent tolerability for each in pancreatic cancer patients receiving chemotherapy. In this phase I trial, we will establish the feasibility for quantifying the effect of the total neoadjuvant therapy/PHL combination on the pancreas secretome as measured by inflammatory & proliferative chemokine & cytokines in pancreatic juice. Establishing a paradigm for “window of opportunity” sampling will allow us to assess our ability to influence the “neighborhood normalizing” hypothesis at the secretome level. Ultimately, this study will serve as a model to treat & monitor in real-time the efficacy for subsequent patients as well as to test new promising therapies in future pancreatic cancer “window of opportunity” trials.