Causes and Consequences of Acid pH in Tumors

肿瘤中酸性 pH 值的原因和后果

• 批准号: 8513139
• 负责人: Robert J. Gillies
• 金额: $ 42.55万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8513139
• 关键词: Acidity; Acidosis; Acids; Adoption; Aerobic; Affect; Bicarbonates; Bolus Infusion; Brain Neoplasms; Breast Cancer Cell; Buffers; Cancer cell line; Catabolism; Cell Line; Cell Proliferation; Cell Survival; Cells; Clinical Trials; Contrast Media; Data; Evolution; Extracellular Space; Genotype; Glucose; Glycolysis; Glycolysis Pathway; Goals; Human; Hypoxia; Image; Infusion procedures; Injection of therapeutic agent; Lung; Malignant Neoplasms; Measurement; Measures; Meta-Analysis; Metabolic; Metabolic Control; Methods; Mitochondria; Modeling; Molecular; Monitor; Motion; Mus; Neoplasm Circulating Cells; Neoplasm Metastasis; Oral; Pathway interactions; Patients; Phenotype; Plant Roots; Process; Production; Proteins; Protocols documentation; Publishing; Radial; Resistance; Series; Solid; Solid Neoplasm; Staging; Tail; Vascular blood supply; Veins; Warburg Effect; Work; Xenograft procedure; abstracting; aerobic glycolysis; base; c-myc Genes; carcinogenesis; design; extracellular; gadolinium 1,4,7,10-tetraazacyclododecane-N,N' ,N' ' ,N' ' ' -tetraacetate; glucose metabolism; imaging modality; improved; in vivo; insight; intervention effect; malignant breast neoplasm; mathematical model; mouse model; neoplastic cell; pressure; programs; research study; spectroscopic imaging; therapy development; tumor; tumor microenvironment; tumor progression

Abstract. The microenvironment of solid cancers is acidic. This is a proposal to continue to investigate the causes and consequences of this acidity. Over the past period of support, significant progress has been made in all three aims to (1) improve methods for measuring pH in vivo, (2) determine the causes of the acidity, and (3) characterize the consequences of this acidity that are relevant to cancer progression. In aim 1, a method has been developed with which to measure pH following a single infusion of a pH-dependent contrast agent cocktail containing Gd-DOTA-4AmP and Dy-DOTA. In aim 2, the root causes of acid pHe have been identified as increased aerobic glucose metabolism (the Warburg Effect), which can be caused by dysregulation in one of six interrelated pathways. Experiments of aim 3 have shown that the acid pH promotes invasion and metastasis and, most importantly, inhibiting this acidity with oral ad lib bicarbonate led to significant reductions in spontaneous metastases and increased survival of mice with breast cancer xenografts. An important addition to this program during the previous period has been the incorporation of mathematical modeling based on somatic evolution. These efforts have provided a theoretical framework important to interpreting experimental results. These models led to the prediction that inhibiting acidosis would inhibit metastasis, as has been observed. A further model to arise from this work is the "evolutionary equivalence principle" that recognizes that Darwinian forces select for phenotype, not genotype, and is thus can explain the multiple molecular mechanisms and pathways associated with increased aerobic glycolysis in tumors. For clarity and consistency, the titles of the aims of the current proposal remain the same, although the foci have been significantly altered to accommodate new data and new insights. Aim 1 will develop a bolus injection approach of a pH-sensitive contrast agent, with an anticipated endpoint of IND filing for imaging tumor pHe with a single agent in humans within the next period of support. Aim 2 will investigate the molecular mechanisms underlying increased glycolysis by cancers by comparing the control strengths of the six interrelated pathways in a panel of derivatized and parental cell lines. Aim 3 will be focused entirely on characterizing and modeling the effect of pH buffering on inhibiting metastasis to better define the boundary conditions and mechanisms of this approach. These will add needed data to planned clinical trials.

抽象的。 实体癌的微环境是酸性的。这是一项继续调查 这种酸性的原因和后果。在过去的支助期间，取得了重大进展。 这三个目的都是为了(1)改进体内pH的测量方法，(2)确定酸度的原因，以及 (3)描述这种酸度与癌症进展相关的后果。在目标1中，一种方法 已经开发出一种在单次注入依赖于pH的造影剂后测量pH的方法 含有Gd-DOTA-4AmP和Dy-DOTA的鸡尾酒。在目标2中，已经确定了酸性苯丙氨酸的根本原因 由于有氧葡萄糖代谢增加(沃伯格效应)，这可能是由一种失调引起的 六条相互关联的路径。目标3的实验表明，酸性pH促进了入侵和 转移，最重要的是，口服随机碳酸氢钠抑制这种酸性导致显著减少。 在乳腺癌移植瘤小鼠的自发转移和提高存活率方面。一个重要的 除了该计划在前一时期已纳入数学建模的基础上 关于体细胞进化的。这些努力为口译提供了一个重要的理论框架 实验结果。这些模型导致预测，抑制酸中毒将抑制转移，因为 已经被观察到了。从这项工作中产生的另一个模型是“进化等价原则” 认识到达尔文的力量是根据表型而不是基因型进行选择的，因此可以解释 肿瘤中有氧糖酵解增加的分子机制和途径。 为清楚和一致起见，当前提案的目标的标题保持不变，尽管 为了适应新的数据和新的见解，焦点已经发生了重大变化。目标一号将开发一种推进剂 注射pH敏感造影剂的途径，预期终点为IND文件成像肿瘤 在接下来的一段时间内，Phe与人类中的单一制剂一起支持。目标2将研究分子 通过比较这六种药物的控制强度，揭示癌症糖酵解增加的机制 一组衍生和亲本细胞系中相互关联的通路。《目标3》将完全集中在 描述和模拟pH缓冲在抑制转移中的作用，以更好地确定边界 这种方法的条件和机制。这些将为计划中的临床试验增加所需的数据。