Causes and Consequences of Acid pH in Tumors

肿瘤中酸性 pH 值的原因和后果

• 批准号: 8322962
• 负责人: Robert J. Gillies
• 金额: $ 8.36万
• 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/8322962
• 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 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; public health relevance; research study; spectroscopic imaging; therapy development; tumor; tumor progression

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Narrative Solid tumors have high metabolic rates and inadequate blood supplies. The combination of these two factors leads to a buildup of acid in extracellular space of the tumors. This acidity is an important component of cancer progression as the cells that adapt to these hostile conditions are more prone to form metastases. This proposal seeks to understand the causes of this tumor acidity and its consequences, with the goal of developing therapies to slow cancer progression in patients. Recently published data show that inhibiting tumor acidity can reduce spontaneous metastases in mice models of breast cancer.

描述（由申请人提供）： 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度的原因和后果的建议。在过去的支持期间，所有三个目标都取得了重大进展：（1）改进体内pH测量方法，（2）确定酸度的原因，（3）表征与癌症进展相关的酸度的后果。在目的1中，已经开发了一种方法，利用该方法在单次输注含有Gd-DOTA-4AmP和Dy-DOTA的pH依赖性造影剂混合物后测量pH。在目标2中，酸性pHe的根本原因已被确定为有氧葡萄糖代谢增加（瓦尔堡效应），其可由六种相关途径之一的失调引起。目的3的实验已经表明，酸性pH促进侵袭和转移，并且最重要的是，用口服自由碳酸氢盐抑制这种酸性导致自发转移的显著减少和具有乳腺癌异种移植物的小鼠的存活率增加。在前一时期，该计划的一个重要补充是纳入了基于体细胞进化的数学建模。这些努力为解释实验结果提供了重要的理论框架。这些模型导致预测抑制酸中毒将抑制转移，如已经观察到的。从这项工作中产生的另一个模型是“进化等效原理”，该原理认识到达尔文力量选择表型，而不是基因型，因此可以解释与肿瘤中有氧糖酵解增加相关的多种分子机制和途径。 为清晰和一致起见，本提案各项目标的标题保持不变，但重点作了重大修改，以适应新的数据和新的见解。目标1将开发一种pH敏感型造影剂的团注方法，预期终点为IND申请，用于在下一个支持期内使用单一造影剂对人体肿瘤pHe进行成像。目标2将通过比较一组衍生细胞系和亲本细胞系中六种相互关联的途径的控制强度，研究癌症增加糖酵解的分子机制。目标3将完全集中在表征和建模pH缓冲对抑制转移的影响，以更好地定义这种方法的边界条件和机制。这些将为计划的临床试验添加所需的数据。 公共卫生关系： 实体瘤具有高代谢率和血液供应不足。这两种因素的结合导致肿瘤细胞外空间中酸的积聚。这种酸性是癌症进展的重要组成部分，因为适应这些不利条件的细胞更容易形成转移。该提案旨在了解这种肿瘤酸性的原因及其后果，目标是开发减缓患者癌症进展的疗法。最近发表的数据表明，抑制肿瘤酸性可以减少乳腺癌小鼠模型的自发转移。