Metabolic regulation of FOLFIRINOX acquired resistance in pancreatic cancer

FOLFIRINOX 在胰腺癌中获得性耐药的代谢调节

• 批准号: 10518247
• 负责人: Pankaj Kumar Singh
• 金额: $ 29.39万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10518247
• 关键词: Acidity; Address; Adenosine; Amino Acids; Anabolism; Arginine; Arginine deiminase; Blood Circulation; Blood Vessels; CRISPR library; CRISPR screen; Cancer Etiology; Cell Line; Cells; Cessation of life; Charge; Chemoresistance; Clinical; Complement; Data; Development; Diagnosis; Diffusion; Epigenetic Process; Event; Feeds; Future; Generations; Genes; Genetic Transcription; Glucose; Glycolysis Inhibition; Human; Hypoxia; Immune; Intercellular Fluid; Malignant neoplasm of pancreas; Mediating; Metabolic; Metabolic Pathway; Metabolism; Myeloid-derived suppressor cells; Oncogenic; Organoids; Oxidative Phosphorylation; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Phenotype; Phosphoglycerate dehydrogenase; Post-Translational Protein Processing; Prediction of Response to Therapy; Production; Prognosis; Proteins; Proteomics; Purines; Regulation; Relapse; Resistance; Resistance development; Role; Serine; Side; Signal Transduction; Site; Specimen; Stromal Neoplasm; T-Lymphocyte; Testing; Therapeutic; Tumor Cell Line; United States; acquired immunity; alpha ketoglutarate; chemotherapy; deprivation; genetic signature; genome-wide; human tissue; improved; insight; knock-down; neoplastic cell; novel; novel therapeutics; pancreatic ductal adenocarcinoma cell; pancreatic neoplasm; patient derived xenograft model; patient prognosis; predictive marker; prevent; protein protein interaction; recruit; response; therapy resistant; tissue resource; treatment response; tumor; tumor microenvironment; tumorigenic

Project Summary: Early systemic dissemination, extraordinary local invasion, late diagnosis, and inadequate response to the existing chemotherapy contribute to poor prognosis for pancreatic ductal adenocarcinoma (PDAC) patients. While pancreatic tumors generally show a low intrinsic response to chemotherapies, most acquire resistance over the course of the treatment. Hence, there is an urgent need to understand the mechanisms contributing to acquired resistance to therapies and to identify novel therapies/therapeutic combinations that would significantly improve survival in patients. We have demonstrated that metabolic reprogramming presents a targetable vulnerability for abrogating acquired resistance and improving the therapy response in PDAC. The therapy resistance depends on both tumor cell-intrinsic mechanisms and a metabolic and signaling crosstalk between tumor cells and tumor microenvironment. Our unbiased preliminary data with multiple human PDAC patient-derived xenograft models identified peptidyl arginine deiminase 1 (PADI1) as the top upregulated gene that correlated significantly with poor patient prognosis. Citrullination or deimination of arginine residues produces a loss of a positive charge, increasing the mass and the acidity of the amino acid side chain, and the post-translational modification results in altered protein-protein interactions, signaling, and transcriptional responses. We noted robust expression of PADI1 in human PDAC tumors and cell lines and a correlation with patient survival. Inhibiting PADI activity or PADI1 knockdown significantly improved the responsiveness of PDAC cell lines and organoids to components of FOLFIRINOX therapy. PADI1 expressing PDAC tumors also demonstrated a significant correlation with the glycolytic phenotype and hypoxia gene signature, showing a reciprocal relationship with oxidative phosphorylation. We also performed an unbiased CRISPR screen and identified novel metabolic vulnerabilities that may be efficacious for co-targeting with agents inhibiting PADI1 downstream metabolic pathways. PADI expression also correlated with the reprogramming of immune and non-immune stroma in the microenvironment. Hence, the proposed project 1 will test the hypothesis if targeting PADI1 or downstream metabolic reprogramming will abrogate the development of resistance to FOLFIRINOX in PDAC. We will also investigate the mechanistic basis of stromal remodeling in PDAC tumors and the stromal reprogramming that contributes to acquired FOLFIRINOX resistance. We propose three specific aims to test the hypothesis. Aim 1 will investigate the efficacy of targeting PADI1 downstream pathways and associated mechanisms of stromal remodeling for abrogating resistance to FOLFIRINOX therapy. Aim 2 will determine the mechanism of tumor-cell intrinsic metabolic reprogramming that also feeds into stromal reprogramming by PADI1. Aim 3 will investigate the efficacy of targeting the pathways identified in Aims 1 and 2 in PDX models and determine clinical correlates utilizing human tissue specimens. These studies will provide novel insights and opportunities to target acquired FOLFIRINOX resistance in PDAC.

项目概要：早期全身性传播、非同寻常的局部侵袭、晚期诊断和不充分 对现有化疗的反应导致胰腺导管腺癌预后不良 （PDAC）患者。虽然胰腺肿瘤通常对化疗表现出较低的内在反应，但大多数 在治疗过程中获得耐药性。因此，迫切需要了解 导致获得性治疗耐药的机制并确定新疗法/治疗方法 组合将显着提高患者的生存率。我们已经证明代谢 重编程提供了消除获得性耐药性和改善治疗的可针对性的脆弱性 PDAC 中的响应。治疗耐药性取决于肿瘤细胞内在机制和代谢 以及肿瘤细胞和肿瘤微环境之间的信号串扰。我们公正的初步数据 多个人 PDAC 患者来源的异种移植模型将肽基精氨酸脱亚胺酶 1 (PADI1) 确定为 上调基因与患者不良预后显着相关。瓜氨酸化或脱亚胺化 精氨酸残基失去正电荷，增加氨基酸的质量和酸度 侧链和翻译后修饰会导致蛋白质-蛋白质相互作用、信号传导和 转录反应。我们注意到 PADI1 在人类 PDAC 肿瘤和细胞系中的强劲表达，并且 与患者生存率的相关性。抑制 PADI 活性或敲除 PADI1 显着改善 PDAC 细胞系和类器官对 FOLFIRINOX 治疗成分的反应。 PADI1表达 PDAC 肿瘤还表现出与糖酵解表型和缺氧基因显着相关 特征，显示与氧化磷酸化的相互关系。我们还进行了公正的 CRISPR 筛选并鉴定出可能对药物联合靶向有效的新型代谢漏洞 抑制 PADI1 下游代谢途径。 PADI 表达还与重编程相关 微环境中的免疫和非免疫基质。因此，拟议项目 1 将检验假设 如果靶向 PADI1 或下游代谢重编程将消除耐药性的发展 到 PDAC 中的 FOLFIRINOX。我们还将研究 PDAC 基质重塑的机制基础 肿瘤和基质重编程有助于获得性 FOLFIRINOX 耐药。我们建议 检验假设的三个具体目标。目标 1 将研究靶向 PADI1 下游的功效 消除 FOLFIRINOX 治疗耐药性的基质重塑途径和相关机制。 目标 2 将确定肿瘤细胞内在代谢重编程的机制，该重编程也进入基质 由 PADI1 重新编程。目标 3 将研究针对目标 1 和 2 中确定的途径的功效 在 PDX 模型中并利用人体组织标本确定临床相关性。这些研究将提供 针对 PDAC 中获得性 FOLFIRINOX 耐药性的新见解和机会。