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，其发病率呈上升趋势 发病率和死亡率。吉西他滨(GEM)是治疗PC的基石，而GEM 耐药性在化疗开始后的几周内产生，导致对 生死存亡。GEM与其他化疗药物联合使用往往会导致严重的毒性， 但存活率没有太大的提高。越来越明显的是，PC患者表现出代谢 会影响他们的预后和生存的损害。事实上，重新编程的新陈代谢是一个 癌细胞的特征，人们对将代谢途径作为一种 改善治疗反应的方法。为此，谷氨酰胺代谢已被广泛研究以 靶向癌细胞增殖。然而，其他氨基酸在调节PC中的作用 发病机制尚不清楚。我们的初步数据提供了令人信服的证据 小鼠体内组氨酸解氨酶(HAL)表达水平较低，组织HAL表达较高 PC患者和人类PC患者与对照组比较。我们对PC细胞系的研究表明，他的 引起细胞毒性，伴随而来的是氨产量的增加。而且，他的In 与GEM联合应用具有更大的细胞毒性，同时IGF-1也有更大的降低。 1R/mTOR/S6K信号转导与单独处理的比较。因此，我们假设他的 和HAL是PC发病机制的新调节剂，针对他的代谢是一种 GEM增强抗癌作用的前景看好。我们将采用营养， 药理学和代谢方法，以确定其作用和机制 他的代谢改变调节了PC对GEM治疗的反应。我们提出了两个具体的 目的：在具体目标1中，我们将确定组氨酸结合的机制 吉西他滨对PC细胞株和PC类有机物的杀伤作用增强 体外培养。在具体目标2中，我们将评估His联合GEM的治疗效果。 在PC的原位和遗传小鼠模型中。总之，这些研究将揭示他的角色 在调节PC细胞新陈代谢方面，确定潜在的机制，并为未来奠定基础 治疗方面的发现。