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

基本信息

项目摘要

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(GEM)一直是PC治疗的基石,但GEM 耐药性在化疗开始后数周内发展,仅对化疗产生适度影响。 生存吉西他滨与其他化疗药物联合使用往往会导致严重的毒性, 生存率没有多大提高。越来越明显的是,PC患者表现出代谢紊乱 可能影响其预后和生存的损伤。事实上,重新编程的新陈代谢是一种 癌细胞的特征,并且对靶向代谢途径作为治疗癌症的方法的兴趣越来越大。 改善治疗反应的方法。为此,谷氨酰胺代谢已被广泛研究, 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强有力的证据, 水平较低,组织组氨酸解氨酶(HAL)表达较高, PC和人类PC患者,与对照组相比。我们在PC细胞系中的研究表明, 诱导细胞毒性,伴随着氨产生的增加。此外,他在 与吉西他滨的组合产生了更大的细胞毒性,伴随着IGF-1的更大降低。 1 R/mTOR/S6 K信号传导与单独治疗相比。因此,我们假设他的 和HAL是PC发病机制的新调节剂,靶向His代谢是治疗PC的有效方法。 有希望的方法,以提高抗癌作用的吉西他滨。我们将采用营养, 药理学和代谢方法来确定的作用和机制, 改变的His代谢调节PC对GEM治疗的反应。我们提出两个具体的 目的:在具体目标1中,我们将确定组氨酸与 吉西他滨对PC细胞系和PC类器官的细胞毒性作用增强, 体外在具体目标2中,我们将评估His与GEM联合的治疗效果 在PC的原位和遗传小鼠模型中。总之,这些研究将揭示他的作用, 在调节PC细胞代谢,确定潜在的机制,并为未来的阶段 治疗发现

项目成果

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Satyanarayana Rachagani其他文献

Satyanarayana Rachagani的其他文献

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{{ truncateString('Satyanarayana Rachagani', 18)}}的其他基金

Targeting tumor and its microenvironment using nanotherapeutics for pancreatic cancer
使用纳米疗法治疗胰腺癌靶向肿瘤及其微环境
  • 批准号:
    10383703
  • 财政年份:
    2020
  • 资助金额:
    $ 16.94万
  • 项目类别:
Targeting tumor and its microenvironment using nanotherapeutics for pancreatic cancer
使用纳米疗法治疗胰腺癌靶向肿瘤及其微环境
  • 批准号:
    10795441
  • 财政年份:
    2020
  • 资助金额:
    $ 16.94万
  • 项目类别:
Targeting tumor and its microenvironment using nanotherapeutics for pancreatic cancer
使用纳米疗法治疗胰腺癌靶向肿瘤及其微环境
  • 批准号:
    10223249
  • 财政年份:
    2020
  • 资助金额:
    $ 16.94万
  • 项目类别:
Targeting tumor and its microenvironment using nanotherapeutics for pancreatic cancer
使用纳米疗法治疗胰腺癌靶向肿瘤及其微环境
  • 批准号:
    10059110
  • 财政年份:
    2020
  • 资助金额:
    $ 16.94万
  • 项目类别:

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