Causes & Consequences of Acid pH in Tumors

描述(由申请人提供)：我们和其他人之前的工作已经证明，实体肿瘤的细胞外pH(Phe)通常是酸性的，也许总是酸性的。这项建议旨在继续我们的研究，以更好地了解酸性苯丙氨酸在癌症进展和治疗的进化动力学中的作用。我们观察到，酸性的Phe对于从原位癌到浸润性癌的转变是重要的，也许是必要的。通过促进侵袭，酸性苯丙氨酸也是转移形成的关键因素。这 Grant在NCI的投资组合中是独一无二的，它专注于肿瘤的PH值，这是癌症的一个基本属性。在其14年的历史中，它围绕三个相互关联的主题组织：1)改进PHE的测量；2)了解酸中毒的原因；以及3)利用酸性Phe的后果来治疗。本组织卓有成效，在这些主题中的每一个方面都有引人注目的新挑战，这些挑战将在下一个支助期得到解决。在过去14年的AIM 1工作中，我们和其他人开发了越来越复杂的方法来测量动物肿瘤模型中的Phe。然而，随着新型酸性pH靶向疗法的出现，迫切需要一种方法来测量人类患者的pH值。因此，我们建议结合核磁共振成像和正电子发射计算机断层成像来预测酸性的“栖息地”。由于这种方法会有一些局限性，我们将继续开发超极化HCO3作为pH显像剂，因为超极化MRI有一个临床轨迹。在目标2的过程中，我们已经定量地确定代谢-血流不匹配是肿瘤酸度的关键驱动因素。然而，在最后的支持期间，人们越来越了解到，肿瘤内存在大量的异质性，不仅在栖息地和基因组学上，而且在代谢谱上也肯定会对肿瘤内的pH产生影响。因此，我们建议通过免疫组织化学和细胞和复杂组织的代谢图谱来发展对这一点的定量理解。这项工作不仅有助于我们对癌症生物学的基本了解，还将识别和测试新的治疗靶点。研究目的3明确了pH对化疗的影响，并发现用缓冲液中和肿瘤酸性也能抑制转移。在过去的支持期间，我们继续研究缓冲疗法，并启动了临床试验。这种方法仍有许多悬而未决的问题，这将是下一个支持期的重点。由于一些令人信服的原因，拟议的工作将专门专注于胰腺导管腺癌(PDAC)。首先是这种癌症迫切需要替代疗法，其次，初步数据表明，区域性酸中毒在PDAC的生物学和临床过程中起着关键作用。我们预计这项工作将导致缓冲疗法组合的生物标记物驱动的临床试验。 在PDAC患者中。

DESCRIPTION (provided by applicant): Prior work by us and others has demonstrated that the extracellular pH (pHe) of solid tumors is commonly, and perhaps always, acidic. This proposal seeks to continue our research to better understand the role of acid pHe in the evolutionary dynamics of cancer progression and therapy. We have observed that an acidic pHe is important, and perhaps necessary, for the transition from an in situ to an invasive cancer. By facilitating invasion, an acidic pHe is also a critical factor in the formation of metastases. This grant is unique within the NCI portfolio by focusing on tumor pH, which is a fundamental property of cancer. Over its 14-year history, it has been organized around three interrelated themes to: 1) improve measurement of pHe; 2) understand the causes of acidosis; and 3) exploit the consequences of acid pHe for therapeutic benefit. This organization has been very productive and there are compelling new challenges in each of these themes that will be addressed in the next period of support. Over the last 14 years of work in Aim 1, we and others have developed increasingly sophisticated methods to measure the pHe in animal tumor models. With the advent of novel acid pH targeted therapies, however, there is a compelling need for methods to measure pH in human patients. We therefore propose to predict the acidic "habitat" using a combination of MRI and PET imaging. Because there will be some limitations to this approach, we will continue to develop hyperpolarized HCO3 as a pH-imaging agent, because there is a clinical trajectory of hyperpolarized MRI. Over the course of Aim 2, we have quantitatively identified that metabolism-perfusion mismatch is a key driver of tumor acidity. However, during the last period of support, it has become increasingly understood that there is a great amount of intra- tumoral heterogeneity, not only in habitats and genomics, but also in metabolic profiles that are sure to have an impact on intratumoral pH. We thus propose to develop a quantitative understanding of this through immunohistochemistry and metabolic profiling of cells and complex tissues. This work will not only contribute to our basic understanding of cancer biology, it will also identify and test novel therapeutic targets. Studies f Aim 3 have defined effects of pH on chemotherapy, and have led to the discovery that neutralization of tumor acidity with buffers also inhibited metastasis. Over the last period of support, we have continued to investigate buffer therapy and have initiated clinical trials. There are still many unanswered questions with this approach, and this will be the focus during the next period of support. The proposed work will focus exclusively on pancreatic ductal adenocarcinoma, PDAC, for a number of compelling reasons. First among these is that alternative therapies are desperately needed for this cancer and, second, preliminary data have demonstrated regional acidosis plays a critical role in the biology and clinical course of PDAC. We expect this work will result in biomarker-driven clinical trials for buffer therapy combinations in PDAC patients.