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

胰腺癌分泌组作为患者基质重编程功效的动态生物标志物

基本信息

批准号：
10663380
负责人：
Paul Michael Campbell
金额：
$ 9.4万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-08 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10663380
关键词：
Address Adjuvant Chemotherapy Affect Biological Markers Biological Specimen Banks Blood specimen Cancer Etiology Cells Cessation of life Chemotherapy and/or radiation Clinical Clinical Trials Combination Drug Therapy Companions Consent Cyst Fluid DNA Desmoplastic Doctor of Philosophy Duct (organ) structure Early Diagnosis Environment Epithelial Cells Epithelium Excision FDA approved Fibroblasts Fibrosis Fox Chase Cancer Center Future Goals Hydroxychloroquine Immune Immunosuppression Inflammatory Knowledge Laboratories Language Letters Liquid substance Losartan Macrophage Malignant Neoplasms Malignant neoplasm of pancreas Measurement Measures Mediator Methodology Methods MicroRNAs Modality Modeling Monitor Natural Killer Cells Neighborhoods Neoadjuvant Therapy Operative Surgical Procedures Outcome Pancreas Pancreatic Adenocarcinoma Pancreatic Cyst Pancreatic duct Pancreatitis Paracrine Communication Patients Pharmaceutical Preparations Pilot Projects Preparation Prior Therapy Protocols documentation RNA Radiation Radiation therapy Reaction Recovery Resistance Sampling Signal Transduction Solid Neoplasm Stromal Cells Stromal Neoplasm Surface Testing Therapeutic Therapeutic Intervention Time Tissues Tumor Markers Untranslated RNA Work cancer cell cancer therapy chemokine chemoradiation chemotherapy clinical trial enrollment cohort cytokine design effective therapy exosome extracellular vesicles feasibility testing innovation neoplastic cell novel novel therapeutics pancreatic cancer patients pancreatic juice pancreatic neoplasm paracrine paricalcitol patient biomarkers peripheral blood phase I trial programs response standard of care therapeutic target treatment response tumor tumor growth tumor microenvironment tumor progression

项目摘要

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.

项目概要/摘要预计胰腺癌很快将成为美国癌症死亡的第二大原因。早期诊断的患者很少，手术是最好的选择，但仅手术很少能治愈，因此，术前检查。化疗加放疗有可能增加长期生存的可能性。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。细胞以促进的方式修改局部邻近细胞（即结缔组织形成或基质），而不是在 Fox Chase Cancer，通常通过特定的癌症相关成纤维细胞 (CAF) 来限制肿瘤生长。马文和康塞塔格林伯格胰腺癌研究所中心，大量的前期工作已经确定了关键胰腺邻近区域、新辅助治疗引起的局部纤维化和患者生存之间的关系。当邻近细胞（包括 CAF、免疫细胞和其他细胞）被上皮细胞和/或术前治疗时，这种局部反应可能会引起治疗抵抗，了解这种关系是关键。在治疗胰腺癌时，有效的治疗必须以邻近细胞的“正常化”为目标恢复其天然的肿瘤抑制活性，但人们对各种旁分泌的影响知之甚少。充当上皮肿瘤细胞、CAF、免疫细胞和其他成分之间语言的介质此外，我们对于趋化因子和细胞因子的理解存在知识空白。胰腺癌新辅助治疗的影响。在这项研究中，我们将确定与肿瘤邻近分泌蛋白信号通路相关的参与者的变化该研究建议测试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措施后，旨在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”来测试三种微环境“正常化”药物（PHL：帕立骨化醇、羟氯喹和氯沙坦）在此阶段接受化疗的每位胰腺癌患者均具有良好的耐受性。在一项试验中，我们将建立量化总新辅助治疗/PHL 组合效果的可行性通过胰腺中炎症和增殖趋化因子和细胞因子测量的胰腺分泌组建立“机会之窗”抽样范例将使我们能够评估我们的影响能力。最终，这项研究将作为分泌组水平的“邻域标准化”假设。实时治疗和监测后续患者的疗效，并测试新的有前景的疗法未来胰腺癌“机会之窗”试验。