Causes and Consequences of Acid pH in Tumors

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性的原因和后果的建议。在过去的支持期间，在以下三个目标方面都取得了重大进展：(1)改进体内pH值的测量方法；(2)确定酸度的原因；(3)确定与癌症进展相关的酸度的后果。在目标1中，发展了一种测量单次输注含有Gd-DOTA-4AmP和Dy-DOTA的pH依赖造影剂鸡尾酒的pH的方法。在目标2中，酸性Phe的根本原因被确定为有氧葡萄糖代谢增加(Warburg效应)，这可能是由六条相互关联的途径中的一条途径的失调引起的。Aim 3的实验表明，酸性pH促进了侵袭和转移，最重要的是，用口服随机碳酸氢盐抑制这种酸性，显著减少了自发转移，提高了乳腺癌移植瘤小鼠的存活率。在前一阶段，这一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一个重要的理论框架。正如已经观察到的那样，这些模型导致了抑制酸中毒将抑制转移的预测。从这项工作中产生的另一个模型是“进化等价原则”，它承认达尔文力量选择的是表型，而不是基因，因此可以解释肿瘤中与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，目前提案的目标标题保持不变，尽管重点已作了重大改动，以适应新的数据和新的见解。AIM 1将开发一种pH敏感造影剂的团注方法，预期终点为在下一个支持期内使用单一试剂在人体内对肿瘤Phe进行成像的IND申请。目的2将通过比较衍生细胞系和亲代细胞系中六条相互关联的通路的控制强度，来研究癌症糖酵解增加的分子机制。目标3将完全集中于描述和模拟pH缓冲在抑制转移中的作用，以更好地定义这一方法的边界条件和机制。这些将为计划中的临床试验增加所需的数据。 公共卫生相关性： 叙述性实体瘤代谢率高，血液供应不足。这两个因素的结合导致了肿瘤细胞外空间的酸性积聚。这种酸性是癌症进展的一个重要组成部分，因为适应这些不利条件的细胞更容易形成转移。这项建议试图了解这种肿瘤酸化的原因及其后果，目的是开发治疗方法来减缓患者的癌症进展。最近发表的数据表明，抑制肿瘤的酸性可以减少乳腺癌模型小鼠的自发转移。

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.