Intratumoral Metabolic Crosstalk Promotes Therapeutic Resistance in Pancreatic Cancer

瘤内代谢串扰促进胰腺癌的治疗耐药

基本信息

批准号：
10305594
负责人：
Costas Andreas Lyssiotis
金额：
$ 37.35万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10305594
关键词：
3-Dimensional Bypass Cancer Etiology Cells Cessation of life Chemoresistance Clinical Clinical Treatment Communication Data Deoxycytidine Deoxycytidine Kinase Diagnosis Disease Drug Delivery Systems Drug Metabolic Detoxication Evolution Fibroblasts Future Generations Human Immune Immunocompetent Impairment Incidence Infiltration Isotopes Label Liquid substance Malignant Neoplasms Malignant neoplasm of pancreas Measures Mediating Medicine Metabolic Metabolic Pathway Metabolism Methods Modeling Molecular Nucleic Acids Nucleosides Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phenotype Phosphotransferases Play Process Prodrugs Production Property Publishing Pyrimidine Nucleosides Reaction Reporting Research Proposals Resistance Role Scheme Signal Pathway Signal Transduction Survival Rate Techniques Testing Therapeutic Agents Thick Toxic effect Translations Tumor-associated macrophages United States Vascularization base cancer cell cell type chemotherapeutic agent chemotherapy clinical application cytotoxic effective therapy gemcitabine in vivo inhibitor insight interstitial macrophage metabolomics mouse model novel nucleoside analog pancreatic cancer cells pancreatic cancer patients pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model pancreatic neoplasm predicting response response standard of care therapeutic evaluation therapy resistant three dimensional cell culture tumor uptake

项目摘要

ABSTRACT Pancreatic cancer is a devastating disease with a five-year survival rate below 10%. One of the main factors underscoring this low survival rate is the lack of effective clinical treatments. The chemotherapy gemcitabine is the most widely used agent for pancreatic cancer due to its well tolerated profile, even though treatment only marginally extends survival. In other cancers, gemcitabine can be very effective. The limited utility of gemcitabine in pancreatic cancer is thought to result from non-cancerous cells in the tumor creating a physical barrier limiting drug delivery. According to this model, chemotherapeutic agents are unable to penetrate the tumor and reach the cancer cells. We found that tumor associated macrophages (TAMs), a non-cancerous immune cell type, abundantly secrete the nucleoside deoxycytidine (dC), and this directly inhibits the cytotoxic activity of gemcitabine. In this research proposal, we will define how dC is made and released by TAMs and how dC is obtained and utilized by pancreatic cancer cells to promote gemcitabine resistance. We will also test the hypothesis that dC release is a TAM property that can be reversed by reprogramming the TAM phenotype. These studies will be accomplished using metabolomics techniques in combination with inhibitors of metabolism and signal transduction. In parallel, we will disrupt TAM-pancreatic cancer dC crosstalk in human patient-derived microtumor models and in syngeneic mouse models to determine the translation value. The clinical application of insights from these studies could have an immediate impact on patients. A means to predict gemcitabine response based on TAM properties and/or to enhance gemcitabine efficacy by targeting the TAM phenotype would increase the utility of this well-tolerated, mainstay treatment option for patients with pancreatic cancer.

抽象的胰腺癌是一种毁灭性疾病，五年生存率低于10％。主要因素之一强调这种低存活率的是缺乏有效的临床治疗。化学疗法吉西他滨是由于其耐受性良好的特征，最广泛使用的胰腺癌药物，即使仅治疗边缘延长生存。在其他癌症中，吉西他滨可能非常有效。有限的效用胰腺癌中的吉西他滨被认为是由肿瘤中的非癌细胞引起的限制药物输送的障碍。根据该模型，化学治疗剂无法穿透肿瘤并到达癌细胞。我们发现肿瘤相关的巨噬细胞（TAMS），一种非癌症免疫细胞类型，大量分泌核苷脱氧胞苷（DC），这直接抑制了细胞毒性吉西他滨的活性。在这项研究建议中，我们将定义DC是如何由TAM和胰腺癌细胞如何获得和利用DC来促进吉西他滨的耐药性。我们还将测试 DC释放是一种TAM特性的假设，可以通过重新编程TAM表型来逆转。这些研究将使用代谢组学技术与抑制剂结合使用代谢和信号转导。同时，我们将破坏人类中的tam-pancreatic DC Crosstalk 患者衍生的微肿块模型和合成小鼠模型以确定翻译值。这这些研究的见解的临床应用可能会对患者产生直接影响。一种手段根据TAM特性预测吉西他滨的响应和/或通过靶向吉西他滨的功效 TAM表型将增加这种耐受性良好的，主要的支柱治疗选项的效用胰腺癌。