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

• 批准号: 10543534
• 负责人: Costas Andreas Lyssiotis
• 金额: $ 36.48万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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/10543534
• 关键词: 3-Dimensional; Anabolism; Bypass; Cancer Etiology; Cells; Cessation of life; Chemoresistance; 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; Macrophage; 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; Penetration; Pharmaceutical Preparations; 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; Therapeutic Agents; Thick; Toxic effect; Translations; Tumor-associated macrophages; United States; Vascularization; cancer cell; cell type; chemotherapeutic agent; chemotherapy; clinic ready; clinical application; cytotoxic; effective therapy; gemcitabine; in vivo; inhibitor; insight; interstitial; metabolomics; mouse model; novel; nucleoside analog; pancreatic cancer cells; pancreatic cancer patients; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; pancreatic neoplasm; pharmacologic; predicting response; response; standard of care; therapeutic evaluation; therapy resistant; three dimensional cell culture; tumor; uptake

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.

摘要 胰腺癌是一种毁灭性的疾病，五年生存率低于10%。的主要因素之一 由于缺乏有效的临床治疗方法，化疗吉西他滨是 由于其良好的耐受性，即使仅治疗， 稍微延长生存时间。在其他癌症中，吉西他滨可能非常有效。有限的效用 吉西他滨在胰腺癌中被认为是由肿瘤中的非癌细胞产生的物理 限制药物输送的屏障。根据该模型，化学治疗剂不能穿透细胞壁。 并到达癌细胞。我们发现，肿瘤相关巨噬细胞（TAMs），一种非癌性巨噬细胞， 免疫细胞类型，大量分泌核苷脱氧胞苷（dC），直接抑制细胞毒性 吉西他滨的活性。在本研究计划中，我们将定义TAM如何制造和释放DC， 胰腺癌细胞如何获得和利用dC来促进吉西他滨耐药性。我们还将测试 假设dC释放是一种TAM特性，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结合以下抑制剂来完成： 代谢和信号转导。与此同时，我们将在人类中破坏TAM-胰腺癌dC串扰。 患者来源的微肿瘤模型和同基因小鼠模型中进行比较，以确定转化值。的 从这些研究中获得的见解的临床应用可能对患者产生直接影响。的手段 基于TAM特性预测吉西他滨应答和/或通过靶向治疗增强吉西他滨疗效 TAM表型将增加这种耐受性良好的主要治疗选择对以下患者的效用： 胰腺癌