Causes and Consequences of Acid pH in Tumors

抽象的。 实体癌的微环境是酸性的。这是一个建议，继续调查， 这是酸的原因和后果。在过去的支持期间，取得了重大进展 在所有三个目标中，（1）改进体内测量pH的方法，（2）确定酸度的原因， (3)描述这种酸性与癌症进展相关的后果。在目标1中， 已经开发了一种用于在单次输注pH依赖性造影剂后测量pH的方法 含有Gd-DOTA-4AmP和Dy-DOTA的混合物。在目标2中，已经确定了酸性pH的根本原因 有氧葡萄糖代谢增加（瓦尔堡效应），这可能是由一种代谢紊乱引起的。 六个相互关联的路径。目的3的实验已经表明，酸性pH促进侵入， 转移，最重要的是，抑制这种酸度与口服自由碳酸氢盐导致显着减少 自发转移和增加乳腺癌异种移植小鼠的存活率。一个重要 除了这个计划在前一时期已经纳入数学建模的基础上， 关于躯体进化这些努力为口译提供了重要的理论框架 试验结果这些模型预测抑制酸中毒将抑制转移， 已经被观察到了。从这项工作中产生的另一个模型是“进化等效原理”， 认识到达尔文的力量选择表型，而不是基因型，因此可以解释多重 肿瘤中有氧糖酵解增加的分子机制和途径。 为清晰和一致起见，本提案各项目标的标题保持不变， 重点已大大改变，以适应新的数据和新的见解。Aim 1将开发一个推注 pH敏感性造影剂的注射方法，预期终点为IND备案用于肿瘤成像 在下一个支持期内，在人类中使用单一药剂。目标2将研究分子 通过比较六种药物的控制强度，探讨癌症糖酵解增加的机制 在一组衍生的和亲本细胞系中的相互关联的途径。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，以更好地定义边界 这种方法的条件和机制。这些将为计划的临床试验添加所需的数据。

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.