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.

项目摘要/摘要预计胰腺癌很快将成为美国癌症死亡的第二大原因。为了很少有早期诊断出的患者是最好的选择，但仅手术很少能治愈。因此，术前化学疗法加放射疗法具有增加长期生存的可能性。一个独特的胰腺癌的标志是“ Desmoplasia”；胰腺癌的非肿瘤细胞扩展和纤维化。癌症细胞以促进这些方式而不是通常限制通过特定癌症相关成纤维细胞（CAF）的肿瘤生长。在Fox Chase Cancer 中心Marvin和Concetta Greenberg胰腺癌研究所，广泛的先前工作已经建立了关键胰腺邻居，新辅助生成的局部纤维化和患者生存之间的关系。当邻域细胞（包括CAF，免疫和其他细胞）被上皮细胞改变时和/或通过术前治疗，这种局部反应可能会耐药性。了解这种关系是关键在治疗胰腺癌和有效治疗时，必须针对邻里细胞的“归一化” 返回其自然肿瘤抑制活性。鲜为人知的是各种旁分泌的影响充当上皮肿瘤细胞，CAF，免疫细胞和其他构成之间语言的介体是肿瘤。此外，我们的知识存在差距是我们了解哪种趋化因子和细胞因子是受胰腺癌新辅助治疗的影响。在这项研究中，我们将确定肿瘤 - 邻居秘密信号播放器相关的变化术前治疗。研究建议测试监视秘密变化的可行性在化学/辐射后和手术前实施的新疗法干预措施之后，旨在重新编程基质及其相互作用。我们将利用手术前的4-6周等待期，作为“机会之窗”，以测试三种微环境“归一化”药物（PHL：副醇，羟基氯喹和Losartan）在接受化学疗法的胰腺癌患者中表现出极好的耐受性。在这个阶段我试验，我们将建立量化总新辅助治疗/PHL组合的效果的可行性通过胰腺炎症和增生的趋化因子和细胞因子在胰腺内分泌组上汁。建立“机会之窗”采样范式，将使我们能够评估自己的影响能力在分泌级别的“邻居规范化”假设。最终，这项研究将作为模型实时治疗和监测后续患者的效率以及测试新的承诺疗法未来的胰腺癌“机会之窗”试验。