Causes and Consequences of Acid pH in Tumors

描述（由申请人提供）： 肿瘤的微环境可能是一个充满敌意的地方，有明显的缺氧和酸性区域。该研究计划的重点是肿瘤pH值，尽管也包括肿瘤氧合的研究。寻求更新资金，以继续改善成像肿瘤pH值的方法（目标1），www.example.com了解在这种恶劣的微环境中酸堆的原因（目标2）和后果（目标3）。在上一个支持期间，我们在所有三个目标方面都取得了重大进展。新的方法已经开发和出口，有氧糖酵解和高酸中毒之间的基本关系被发现，酸堆在赋予耐电离药物的作用的特点。根据这些最后的发现，正在计划一项临床试验，以提高代谢碱化米托蒽醌治疗的疗效。一本书和27份手稿已出版、正在印刷或已提交。在下一个支持期的目标1中，我们建议开发一类令人兴奋的新的MRI敏感的含Gd的pH报告者，其有望以非常高的时空分辨率成像pH。将花费大量精力开发最终适用于临床的定量方法。目标2和3的实验将集中于测试一种新的模型，该模型将肿瘤中的缺氧和酸性视为选择性压力，驱动肿瘤表型从良性演变为转移性。该模型提出，短暂缺氧-缺氧反应元件的失调，HIF-1 α->有氧糖酵解->胃酸过多->蛋白酶->外渗->定植期间的存活之间存在功能联系。这些连接中的每一个都在文献中被观察到，但是还没有在单个系统中被测试。这种模型可以解释为什么在转移性癌症中通常观察到氟脱氧葡萄糖的摄取升高。目的2将使用原代和已建立的人乳腺癌细胞确定HIF-1 α、有氧糖酵解升高、转移潜能和肿瘤中的强酸堆之间是否存在功能性联系。目的3将确定糖酵解、酸堆和转移在外渗和定植水平上是否存在功能性联系。虽然具体的假设将被测试，实验的目的是产生重要的信息，即使假设是不正确的。

DESCRIPTION (provided by applicant): The microenvironment of tumors can be a hostile place, with significant regions that are hypoxic and acidic. The focus of this research program is on the tumor pH, although studies of tumor oxygenation are also included. Renewal funding is sought to continue improving methods for imaging tumor pH (Aim 1), and.to understand the causes (Aim 2) and consequences (Aim 3) of acid pile in this hostile microenvironment. During the last period of support we made significant advances in all three aims. New methods have been developed and exported, a fundamental relationship between aerobic glycolysis and hyperacidosis was uncovered, and the effect of acid pile in conferring resistance to ionizable drugs was characterized. From these last findings, a clinical trial is being planned to enhance the efficacy ofmitoxantrone therapy with metabolic alkalinization. One book and 27 manuscripts have been published, are in press or have been submitted. In Aim 1 of the next period of support, we propose to develop an exciting new class of MRI-sensitive Gd-containing pH reporters which hold promise for imaging pH with very high spatio-temporal resolution. A significant effort will be spent developing quantitative methods that would eventually be appropriate for the clinic. Experiments in aims 2 & 3 will focus on testing a novel model which treats the hypoxia and acidity in tumors as selective pressures that drive the evolution of the tumor phenotype from benign to metastatic. The model proposes that there are functional connections between transient hypoxia --_ dysregulation of the hypoxia response element, HIF-1alpha-> aerobic glycolysis-> hyperacidity-> proteases-> extravasation-> survival during colonization. Each of these connections has been observed in the literature, but has not been tested in a single system. Such a model could explain why elevated uptake of flurodeoxyglucose is commonly observed in metastatic cancers. Aim 2 will determine if there are functional connections between HIF-1alpha, elevated aerobic glycolysis, metastatic potential and hyperacidic pile in tumors using primary and established human breast cancer cells. Aim 3 will determine if there are functional connections between glycolysis, acid pile and metastasis at the levels of extravasation and colonization. Although specific hypotheses will be tested, experiments are designed to yield important information even if the hypotheses are not true.