Altered Histidine Metabolism in Pancreatic Cancer: A Novel Metabolic Target to Enhance Gemcitabine Efficacy

胰腺癌中组氨酸代谢的改变：增强吉西他滨疗效的新代谢靶点

• 批准号: 9893865
• 负责人: Satyanarayana Rachagani
• 金额: $ 16.94万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893865
• 关键词: Address; Affect; Amino Acids; Ammonia; Apoptosis; Attenuated; Biochemical Pathway; Branched-Chain Amino Acids; Cancer Etiology; Cancer cell line; Catabolism; Cell Cycle Arrest; Cell Death; Cell Proliferation; Cell Survival; Cells; Cessation of life; Combined Modality Therapy; Cytotoxic agent; Data; Dietary Intervention; Disease; Drug resistance; Effectiveness; Enzymes; Essential Amino Acids; Exhibits; FRAP1 gene; Fluorouracil; Future; Genetic; Genetic Models; Genus Hippocampus; Glutamine; Glycolysis; Growth; Histidine; Histidine Ammonia-Lyase; Histidine Metabolism Pathway; Human; Impairment; In Vitro; Incidence; Individual; Insulin-Like-Growth Factor I Receptor; Leucovorin; Malignant Neoplasms; Malignant neoplasm of pancreas; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolic stress; Metabolism; Mitochondria; Mus; Neoplasm Metastasis; Non-Insulin-Dependent Diabetes Mellitus; Normal Cell; Nutritional; Obesity; Organoids; Outcome; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacology; Plasma; Play; Production; Proteins; Research; Resistance; Resistance development; Respiration; Risk; Role; Serum; Signal Transduction; Supplementation; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; Treatment Efficacy; Treatment Failure; Tumor Volume; United States; amino acid metabolism; anti-cancer; cancer cell; cancer therapy; chemotherapeutic agent; chemotherapy; cytotoxic; cytotoxicity; effectiveness evaluation; gemcitabine; human tissue; improved; interest; irinotecan; metabolomics; mortality; mouse model; new combination therapies; novel; novel therapeutics; nutritional approach; outcome forecast; oxaliplatin; pancreatic cancer cells; pancreatic cancer model; pancreatic cancer patients; pancreatic neoplasm; protein expression; response; symptomatic improvement; tumor growth; tumor metabolism; uptake

Project Summary Pancreatic cancer (PC) is one of the most lethal malignancies in the United States with a rising incidence and mortality. Gemcitabine (GEM) has been the cornerstone for PC treatment but GEM resistance develops within weeks of chemotherapy initiation, resulting in only a modest impact on survival. Combining GEM with other chemotherapeutic drugs often leads to severe toxicity, without much improvement in survival. It is becoming clear that PC patients exhibit metabolic impairments that can impact their prognosis and survival. In fact, reprogrammed metabolism is a feature of cancer cells and there is an escalated interest in targeting metabolic pathways as a way to improve therapy response. To this end, glutamine metabolism has been widely studied to target cancer cell proliferation. However, the role of other amino acids in modulating PC pathogenesis is still unclear. Our preliminary data provide compelling evidence that serum His level is lower and tissue histidine ammonia lyase (HAL) expression is higher in mice exhibiting PC and human PC patients, compared to controls. Our studies in PC cell-lines showed that His induces cytotoxicity, with a concomitant increase in ammonia production. Moreover, His in combination with GEM exerted a greater cytotoxicity accompanied by a greater reduction in IGF- 1R/mTOR/S6K signaling compared to individual treatments. Therefore, we hypothesize that His and HAL are novel regulators of PC pathogenesis and that targeting His metabolism is a promising approach to enhance the anti-cancer effects of GEM. We will employ nutritional, pharmacological, and metabolic approaches to determine the role and mechanisms by which altered His metabolism regulates the response of PC to GEM therapy. We propose two specific aims: In Specific Aim 1, we will determine the mechanisms by which histidine in combination with gemcitabine exerts enhanced cytotoxic effects against PC cell-lines and PC organoids in vitro. In Specific Aim 2, we will evaluate the therapeutic efficacy of His in combination with GEM in orthotopic and genetic mouse models of PC. Altogether, the studies will uncover the role of His in modulating PC cell metabolism, identify potential mechanisms, and set the stage for future therapeutic discoveries.

项目摘要 胰腺癌（PC）是美国最致命的恶性肿瘤之一 发病率和死亡率。吉西他滨（宝石）一直是PC处理的基石，但宝石 抗药性在化疗开始后数周就会发展，仅对 生存。将宝石与其他化学治疗药物相结合通常会导致严重毒性， 生存没有太大改善。很明显，PC患者表现出代谢 可能影响其预后和生存的障碍。实际上，重编程的代谢是 癌细胞的特征，并且对以代谢途径为目标有兴趣升级 改善治疗反应的方法。为此，谷氨酰胺代谢已被广泛研究到 靶癌细胞增殖。但是，其他氨基酸在调节PC中的作用 发病机理仍不清楚。我们的初步数据提供了令人信服的证据 水平较低，在表现出的小鼠中，组织组氨酸氨裂解酶（HAL）表达较高 与对照组相比，PC和人类PC患者。我们在PC细胞线上的研究表明他 诱导细胞毒性，氨产生的增加。而且，他的进来 与GEM相结合，施加了更大的细胞毒性，伴随着IGF-的降低较大 与单个治疗相比，1R/mTOR/S6K信号传导。因此，我们假设他的 HAL是PC发病机理的新型调节剂，靶向他的代谢是 有前途的方法来增强宝石的抗癌作用。我们将采用营养， 确定作用和机制的药理和代谢方法 改变了他的新陈代谢可以调节PC对宝石治疗的反应。我们提出了两个特定的 目的：在特定目标1中，我们将确定组氨酸组合的机制 吉西他滨发挥对PC细胞线和PC器官的细胞毒性作用增强 体外。在特定的目标2中，我们将评估他与宝石结合使用的治疗功效 在PC的原位和遗传小鼠模型中。总之，研究将揭示他的作用 在调节PC细胞代谢，识别潜在机制并为将来奠定阶段 治疗发现。