Causes & Consequences of Acid pH in Tumors

原因

• 批准号: 9095238
• 负责人: Robert J. Gillies
• 金额: $ 48.88万
• 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 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9095238
• 关键词: Acid-Base Equilibrium; Acidity; Acidosis; Acids; Address; Affect; Alternative Therapies; Animal Model; Animals; Area; Bicarbonates; Biological Models; Biology; Biopsy; Buffers; Cancer Biology; Cells; Chronic; Clinic; Clinical; Clinical Trials; Coculture Techniques; Combined Modality Therapy; Complex; Cultured Cells; Data; Desmoplastic; Development; Diffusion; Diffusion Magnetic Resonance Imaging; Dose; Evolution; Fermentation; Formulation; Genomics; Glucose; Glycolysis; Goals; Grant; Growth; Habitats; Health; Human; Image; Imidazole; Immunohistochemistry; In Situ; Infiltration; Knowledge; Lead; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of pancreas; Maps; Measurement; Measures; Metabolic; Metabolism; Methods; Modeling; Neoplasm Metastasis; Normal Cell; Normal tissue morphology; Oral; Pancreatic Ductal Adenocarcinoma; Patients; Perfusion; Phase I Clinical Trials; Physiologic pulse; Play; Positron-Emission Tomography; Property; Reaction; Recording of previous events; Regimen; Research; Resistance; Role; Second Primary Cancers; Signal Transduction; Solid Neoplasm; Stromal Cells; System; Testing; Therapeutic; Tissues; Toxic effect; Translating; Tromethamine; Tumor Cell Invasion; Vision; Work; base; biomarker-driven; cancer cell; cancer imaging; cancer therapy; cell type; chemotherapy; clinically relevant; expectation; extracellular; imaging agent; improved; in vivo; inhibitor/antagonist; metabolic profile; molecular imaging; mouse model; mutualism; new therapeutic target; novel; prevent; programs; spectroscopic imaging; success; targeted treatment; temporal measurement; therapeutic development; tumor; tumor growth; tumor heterogeneity; tumor progression; uptake

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.

描述（由申请人提供）：我们和其他人之前的工作已经证明，实体瘤的细胞外 pH (pHe) 通常（也许总是）呈酸性。该提案旨在继续我们的研究，以更好地了解酸性 pHe 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 pHe 对于从原位癌症向侵袭性癌症的转变很重要，而且可能是必要的。通过促进侵袭，酸性 pHe 也是转移形成的关键因素。这 这笔资金在 NCI 投资组合中是独一无二的，它专注于肿瘤 pH 值，这是癌症的基本属性。在其 14 年的历史中，它围绕三个相互关联的主题组织起来：1）改进 pHe 的测量； 2）了解酸中毒的原因； 3) 利用酸性 pHe 的影响来获得治疗效果。该组织非常富有成效，并且每个主题都存在令人信服的新挑战，这些挑战将在下一个支持期间得到解决。在过去 14 年的目标 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 值靶向疗法的出现，迫切需要测量人类患者 pH 值的方法。因此，我们建议结合 MRI 和 PET 成像来预测酸性“栖息地”。由于这种方法存在一些局限性，我们将继续开发超极化 HCO3 作为 pH 成像剂，因为超极化 MRI 存在临床轨迹。在目标 2 的过程中，我们定量地确定了代谢-灌注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，人们越来越认识到肿瘤内存在大量异质性，不仅在栖息地和基因组学方面，而且在代谢特征方面也存在这种异质性，这些异质性肯定会对瘤内 pH 值产生影响。因此，我们建议通过细胞和复杂组织的免疫组织化学和代谢分析来定量了解这一点。这项工作不仅有助于我们对癌症生物学的基本了解，还将确定和测试新的治疗靶点。研究 f 目标 3 明确了 pH 对化疗的影响，并发现用缓冲液中和肿瘤酸度也能抑制转移。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。这种方法仍有许多未解决的问题，这将是下一个支持期间的重点。出于许多令人信服的原因，拟议的工作将专门关注胰腺导管腺癌（PDAC）。首先，这种癌症迫切需要替代疗法；其次，初步数据表明局部酸中毒在 PDAC 的生物学和临床过程中发挥着关键作用。我们预计这项工作将导致缓冲疗法组合的生物标志物驱动的临床试验 在 PDAC 患者中。