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: 10707541
• 负责人: Pankaj Kumar Singh
• 金额: $ 24.65万
• 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/10707541
• 关键词: Acidity; Address; Adenosine; Amino Acids; Anabolism; Arginine; Arginine deiminase; Blood Vessels; CRISPR library; CRISPR screen; Cancer Etiology; Cell Line; Cells; Cessation of life; Charge; Chemoresistance; Circulation; Clinical; Complement; Data; Development; Diagnosis; Diffusion; Epigenetic Process; Event; Feeds; Future; Generations; Genes; Genetic Transcription; Glucose; Glycolysis Inhibition; Human; Hypoxia; Immune; Intercellular Fluid; Invaded; 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-Cell Activation; Testing; Therapeutic; United States; acquired immunity; alpha ketoglutarate; chemotherapy; deprivation; ecto-nucleotidase; 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; programs; 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.

项目摘要：早期全身传播，特殊的局部入侵，晚期诊断和不足 对现有化疗的反应导致胰腺导管腺癌的预后不良 （PDAC）患者。虽然胰腺肿瘤通常对化学疗法表现出固有反应较低，但大多数 在治疗过程中获得阻力。因此，迫切需要了解 有助于获得疗法的耐药性并确定新型疗法/治疗性的机制 可以显着提高患者生存的组合。我们已经证明了代谢 重新编程提出了一个可取消获得的抗药性和改善治疗的目标脆弱性 PDAC的响应。耐药性取决于肿瘤细胞内部机制和代谢 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 多个人类PDAC患者衍生的异种移植模型鉴定出肽基精氨酸脱氨酶1（PADI1）为 与患者预后不良显着相关的上调基因。柠檬化或脱水 精氨酸残基会产生正电荷的损失，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 转录响应。我们注意到PADI1在人PDAC肿瘤和细胞系中的强劲表达以及A 与患者的生存相关。抑制PADI活性或PADI1敲低可显着改善 PDAC细胞系和类器官对FOLFIRINOX治疗的成分的反应性。 PADI1表达 PDAC肿瘤还表现出与糖酵解表型和缺氧基因的显着相关性 签名，显示与氧化磷酸化的相互关系。我们也表演了公正 CRISPR屏幕并确定了新型的代谢脆弱性，这些脆弱性可能有效地与代理商共同靶向 抑制PADI1下游代谢途径。 PADI表达也与重新编程有关 微环境中的免疫和非免疫基质。因此，拟议的项目1将检验假设 如果靶向PADI1或下游代谢重编程将消除阻力的发展 到PDAC中的folfirinox。我们还将研究PDAC中基质重塑的机械基础 肿瘤和基质重编程有助于获得的folfirinox耐药性。我们建议 三个特定的目的是检验假设。 AIM 1将研究靶向PADI1下游的功效 基质重塑的途径和相关机制，以消除对Folfirinox治疗的抗性。 AIM 2将确定肿瘤细胞固有代谢重编程的机制，该重编程也会进食基质 通过PADI1重新编程。 AIM 3将研究目标1和2中确定的途径的功效 在PDX模型中，确定使用人体组织标本的临床相关。这些研究将提供 PDAC中靶向靶向获得的folfirinox抗性的新颖见解和机会。