Targeting pancreatic cancer energy metabolism, tumor growth, and metastasis

描述（由申请人提供）：癌症治疗的新兴研究集中在利用癌细胞和正常细胞代谢之间的生化差异。瓦尔堡效应是许多恶性肿瘤细胞中的根本性变化，是能量代谢从氧化磷酸化到有氧糖酵解的转变。通常的看法是，这种代谢重编程提供了不受调节的细胞生长、侵袭和转移所需的细胞能量。人胰腺导管腺癌（PDAC）是一种不可治愈的高度侵袭性人类癌症。75-80%的恶性PDAC患者在初次诊断时的中位生存期为6个月。使用溶细胞药物吉西他滨的标准化疗提供了轻微的生存益处。因此，对于治疗胰腺癌患者的新疗法存在明确无误且关键的未满足的需求。本项目的总体目标是开发新的治疗方法来抑制PDAC恶性肿瘤。该研究的意义在于使用相对无毒的靶向胰腺癌的阳离子药物与糖酵解和氨解能量代谢抑制剂联合使用，以减少胰腺癌细胞的增殖和转移。总体假设是糖酵解、组胺分解和/或线粒体代谢抑制剂与标准疗法的组合将消耗ATP，降低体外能量感应、增殖和迁移，并抑制体内有氧糖酵解和人PDAC肿瘤生长和转移。目标1中的研究将使用创新的高通量和基于质谱的代谢组学方法，研究用靶向谷氨酸的阳离子试剂和/或能量代谢抑制剂处理的人原代PDAC细胞中糖酵解、三羧酸循环和精氨酸分解的生物能量变化。目的2将使用细胞培养方法来确定生物能量代谢抑制剂在激活能量调节信号通路和改变PDAC生长，侵袭和迁移中的作用。目标3将使用临床前超极化磁共振和生物发光成像技术来筛选抑制能量代谢的靶向药物的体内疗效，单独或与传统化疗联合使用，以减轻PDAC的生长和转移。这项工作的总体影响是双重的：首先，它将促进我们对胰腺癌恶性肿瘤中代谢，能量学和能量传感作用的理解，其次，它将产生抑制能量产生的药物的设计和测试，最终可能转化为临床。

DESCRIPTION (provided by applicant): Emerging research in cancer therapy is focused on exploiting the biochemical differences between cancer cell and normal cell metabolism. The Warburg effect is a fundamental change in many malignant cancer cells and is the shift in energy metabolism from oxidative phosphorylation to aerobic glycolysis. The common perception is that this metabolic reprogramming provides the cellular energy required for unregulated cell growth, invasion, and metastasis. Human pancreatic ductal adenocarcinoma (PDAC) is an incurable and highly aggressive human cancer. The median survival of the 75-80% of patients with malignant PDAC at the time of initial diagnosis is 6-months. Standard chemotherapy with the cytolytic drug gemcitabine provides a slight survival benefit. Thus, there is an unmistakable and critical unmet need for new therapies to treat patients with pancreatic cancer. The overall goal of this project is to develop new therapeutic approaches to inhibit PDAC malignancy. The significance of the proposed work lies in the use of relatively nontoxic mitochondria-targeted cationic drugs in combination with glycolytic and glutaminolytic energy metabolism inhibitors to decrease pancreatic cancer cell proliferation and metastasis. The overarching hypothesis is that a combination of glycolytic, glutaminolytic, and/or mitochondrial metabolism inhibitors with standard therapies will deplete ATP, decrease energy sensing, proliferation, and migration in vitro, and inhibit aerobic glycolysis and human PDAC tumor growth and metastasis in vivo. Studies in Aim 1 will use innovative high-throughput and mass spectroscopy-based metabolomics approach to investigate bioenergetic changes in glycolysis, tricarboxylic acid cycle, and glutaminolysis in human primary PDAC cells treated with mitochondria-targeted cationic agents, and/or inhibitors of energy metabolism. Aim 2 will use cell culture approaches to define the role for bioenergetic metabolism inhibitors in activating energy regulatory signaling pathways and altering PDAC growth, invasion, and migration. Aim 3 will use preclinical hyperpolarized magnetic resonance and bioluminescence imaging techniques to screen the in vivo efficacy of targeted drugs that inhibit energy metabolism, alone or in combination with traditional chemotherapy to mitigate PDAC growth and metastasis. The overall impact of the proposed work is two-fold: First, it will advance our understanding of the role of metabolism, energetics, and energy sensing in pancreatic cancer malignancy and second it will engender the design and testing of drugs that stifle energy production and which may ultimately be translated to the clinic.