Targeting pyrimidine biosynthesis in pancreatic ductal adenocarcinoma

胰腺导管腺癌中靶向嘧啶生物合成

基本信息

批准号：
10672389
负责人：
Nicholas James Mullen
金额：
$ 5.27万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-12 至 2025-07-11
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10672389
关键词：
Abraxane Address Affect Agammaglobulinaemia tyrosine kinase American Anabolism Animal Model Antineoplastic Agents Automobile Driving Biochemical Biological Assay Cancer Etiology Cell Line Cell Proliferation Cell Survival Cells Cessation of life Clinical Clinical Trials Clinical effectiveness Combined Modality Therapy Deoxyribonucleosides Dependence Dihydroorotate Dehydrogenase Inhibitor Dihydroorotate dehydrogenase Disease Down-Regulation Drug Combinations Drug Compounding Drug Targeting Drug usage Effectiveness Enzymes FDA approved Follow-Up Studies Genes Genetic Genetic Transcription Glucose Goals Harvest Human Hyperactivity Immune response Immune system Immunocompetent Immunocompromised Host Implant In Vitro Isotope Labeling Label Malignant Neoplasms Malignant neoplasm of pancreas Mediating Metabolic Metabolic Pathway Metabolism Monitor Mus Nucleosides Nucleotide Biosynthesis Nucleotides Nutrient Oncogenic Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Pattern Pharmaceutical Preparations Pharmacotherapy Phosphorylation Phosphotransferases Population Process Proliferating Proteins Pyrimidine Pyrimidine Nucleosides Pyrimidine Nucleotides Quality of life Resistance Ribose Signal Pathway Signal Transduction Site Solid Survival Rate System Toxic effect Treatment Efficacy Tumor Tissue Tumor-infiltrating immune cells Tyrosine Kinase Inhibitor Validation anticancer treatment base cancer cell cancer type chemotherapy combat combinatorial deprivation design effective therapy efficacy evaluation efficacy testing enzyme pathway experimental group experimental study genotoxicity implantation improved in vivo in vivo evaluation inhibitor inorganic phosphate kinase inhibitor metabolic phenotype metabolomics mouse model novel nucleotide metabolism pancreatic ductal adenocarcinoma cell pre-clinical resistance mechanism response single-cell RNA sequencing small molecule standard of care targeted treatment transcriptome sequencing transcriptomics treatment strategy tumor tumor growth tumor microenvironment tumor progression uptake

项目摘要

Project Summary Pancreatic ductal adenocarcinoma (PDAC) is almost universally lethal and is projected to become the second-leading cause of cancer related deaths in the US by 2030. Conventional (genotoxic) chemotherapy approaches that make up the current standard of care are mostly ineffective and prolong survival of advanced PDAC patients by less than one year on average. Similarly, small molecule drugs targeting aberrantly activated oncogenic signaling pathways have shown disappointing clinical results and accordingly have failed to gain FDA approval for PDAC. An alternative strategy to these two approaches is to exploit metabolic dependencies that are unique to malignant cells by virtue of their deranged cellular metabolism. While there are well-characterized resistance mechanisms to genotoxic and targeted therapies, deprivation of certain nutrients critical for proliferation of malignant cells appears to be an insurmountable barrier for cancer progression. However, cells have redundant means of acquiring these critical nutrients, and so inhibition of a single metabolic enzyme is generally not sufficient to deny them to cancer cells. Thus, combinatorial blockade of multiple metabolic pathways could be required to impose deficiency of key metabolites on malignant cells. Pyrimidine nucleotides represent a class of metabolites that has been shown in numerous studies to be essential for PDAC and a host of other malignancies. Importantly, there are several clinical grade inhibitors of pyrimidine synthesis enzymes that have shown preclinical promise as anticancer agents. However, these drugs have uniformly failed to show efficacy in clinical trials in which they were used as monotherapy against various malignancies. One potential explanation for this is that there are two major pathways by which cells generate nucleotides, termed the de novo and salvage pathways, and these inhibitors block the key de novo pathway enzyme dihydroorotate dehydrogenase (DHODH), thus leaving the salvage pathway fully intact. We’ve characterized the response of various PDAC cell lines to the DHODH inhibitor brequinar (BQ). We found that some PDAC cell lines are highly resistant to BQ in cell viability assays compared to their more sensitive counterparts. We then screened some 350 known kinase inhibitor compounds to probe for any that could restore BQ sensitivity in our resistant PDAC cell lines, and this nominated the preclinical BTK inhibitor CNX-774 as the strongest hit. Follow-up studies have shown that combined BQ/CNX-774 treatment leads to profound cell viability loss and pyrimidine depletion, compared to either drug alone, in BQ-resistant PDAC cells. Furthermore, we have strong evidence that CNX-774 is acting in an off-target manner to inhibit pyrimidine salvage. Thus, the goal of this study is to uncover the mechanism by which CNX-774 is sensitizing PDAC cells to BQ and determine if this drug combination is efficacious in our preclinical PDAC mouse models. Our goal is to provide preclinical support for this metabolic combination therapy as a potential PDAC treatment.

项目摘要胰腺导管腺癌（PDAC）几乎是普遍致命的，预计将成为到2030年，美国与癌症相关死亡的第二个领先原因。常规（遗传毒性）化学疗法构成当前护理标准的方法主要是无效的，并且先进的延长生存 PDAC患者平均每年不到一年。同样，针对异常激活的小分子药物致癌信号通路已显示出令人失望的临床结果，因此未能获得 FDA批准PDAC。这两种方法的另一种策略是利用代谢依赖性由于恶性细胞的魔力破坏性的细胞代谢是独有的。虽然对遗传毒性和靶向疗法有良好的抗药性机制，但剥夺某些对于恶性细胞增殖至关重要的营养物质似乎是癌症无法克服的障碍进展。然而，细胞具有获取这些关键营养素的冗余含义，因此抑制A 单一代谢酶通常不足以将其拒绝癌细胞。那，组合封锁可能需要多种代谢途径在恶性细胞上施加关键代谢物的缺乏。嘧啶核苷酸代表一类代谢产物，在许多研究中已显示为对于PDAC和许多其他恶性肿瘤至关重要。重要的是，有几种临床等级抑制剂嘧啶合成酶已显示为抗癌药。但是，这些药物在临床试验中均未显示出效率，在这些试验中，它们被用作单一疗法反对各种恶性肿瘤。一个潜在的解释是，有两种主要途径产生核动脉，称为从头和打捞途径，这些抑制剂阻止了钥匙。途径二氢易能酸酯脱氢酶（Dhodh），因此使打捞途径完全完整。我们已经表征了各种PDAC细胞系对Dhodh抑制剂Brequinar（BQ）的响应。我们发现某些PDAC细胞系在细胞活力测定中对BQ具有高度抗性敏感的对应物。然后，我们筛选了约350个已知的激酶抑制剂化合物，以探测任何可以在我们的抗性PDAC细胞系中恢复BQ敏感性，并提名临床前BTK抑制剂 CNX-774作为强烈的命中。后续研究表明，BQ/CNX-774的联合治疗导致与单独使用的PDAC相比细胞。此外，我们有强有力的证据表明CNX-774正在以非目标抑制的方式作用嘧啶挽救。这是这项研究的目的是发现CNX-774敏感的机制 PDAC细胞至BQ，并确定在我们的临床前PDAC小鼠模型中这种药物组合是否有效。我们的目标是为这种代谢组合疗法作为潜在的PDAC治疗提供临床前支持。