Profiling chemical tumor microenvironment: application for diagnostics & therapy

分析肿瘤化学微环境：诊断应用

• 批准号: 9172930
• 负责人: Valery V Khramtsov
• 金额: $ 34.1万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9172930
• 关键词: Acidosis; Address; Affect; Bicarbonates; Biochemical Genetics; CD3 Antigens; Carbogen; Carbon Dioxide; Cell Survival; Characteristics; Chemicals; Clinical; Complement; Data; Dependence; Diagnostic; Diagnostic Neoplasm Staging; Diet; Drug Metabolic Detoxication; Electron Spin Resonance Spectroscopy; Electrons; Exposure to; Female; Functional Imaging; Functional disorder; Future; Glutathione; Goals; Heterogeneity; Histologic; Homeostasis; Human; Hypoxia; Image; Imaging Techniques; Knowledge; Literature; Magnetic Resonance; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Maps; Measurement; Measures; Metabolism; Methodology; Methods; Monitor; Mus; Normal Cell; Normal tissue morphology; Nuclear Magnetic Resonance; Outcome; Oxidation-Reduction; Pattern; Physiologic pulse; Play; Procedures; Prognostic Factor; Property; Protons; Publishing; Relaxation; Resistance; Role; Sampling; Signal Transduction; Techniques; Technology; Testing; Therapeutic Intervention; Time; Tissues; Transgenic Mice; Treatment Efficacy; Tumor Tissue; Tumor stage; abstracting; analog; angiogenesis; anti-cancer therapeutic; base; breast lesion; cancer cell; cancer therapy; chemotherapy; contrast enhanced; design; docetaxel; extracellular; improved; in vivo; innovation; inorganic phosphate; malignant breast neoplasm; mouse model; phenylalanylphenylalanine; prevent; sensor; therapeutic effectiveness; tumor; tumor microenvironment

Project Summary/Abstract Today it is becoming widely recognized that malignant cells very often behave differently depending on their specific tissue microenvironment (TME). Here we hypothesized Janus-faced properties of tumor TME proposing that specific patterns of TME oxygenation, extracellular pH (pHe), inorganic phosphate (Pi), redox and glutathione (GSH) homeostasis act to utilize an orchestrated mechanism to promote cancer cell survival while at the same time being highly toxic and mutagenic for normal cells. The overall goal of this project is to enable innovative magnetic resonance methods for in vivo multifunctional profiling of chemical TME to improve prediction power of early diagnostics for the malignant transition and for future rational design of TME-targeted anticancer therapeutics. The specific aims are: (SA1) To advance magnetic resonance technology and paramagnetic probes for in vivo real-time tissue microenvironment profiling. The paramagnetic probes for multifunctional measurements using Electron Paramagnetic Resonance (EPR) and Proton-Electron Double- Resonance imaging (PEDRI) techniques will be advanced to perform in vivo real-time TME profiling. Namely, trityl probes for concurrent monitoring of pO2, pHe and Pi, and nitroxide probes for pH, GSH and reducing capacity measurements will be optimized. SA 2: To perform in vivo tumor microenvironment profiling as the tumor progresses to malignancy. The array of the probes from (SA1) will be used to perform chemical TME profiling as the mammary tumors progress to malignancy using our colony of PyMT transgenic mice which spontaneously develop breast cancer and emulate human tumor staging. In addition to L-band EPR spectroscopic measurements, PEDRI functional mapping will be used to assess probe distribution and functional heterogeneity of tumor TME. Dynamic contrast-enhanced (DCE) MRI will be used to quantify tumor spatial heterogeneity. SA 3: To identify prognostic factors and evaluate efficacy of tissue microenvironment manipulation. Normalizing chemical TME may provide a new basis for anticancer TME-targeted therapeutic interventions. In SA 3A we will perform TME manipulation alone, and in combination with standard chemotherapy in SA 3B. We expect that the procedures aimed to prevent/compensate tissue hypoxia and acidosis will also affect tissue redox, Pi and GSH, and improve the outcome in a mouse model of pre-cancer breast lesions. In Aim 3B, we will test our hypothesis that TME chemical normalization will augment therapeutic effectiveness using the standard chemotherapy, docetaxel, to address the important clinical problem of tumor detoxification and chemotherapy resistance.

项目总结/摘要 今天，人们越来越广泛地认识到，恶性细胞往往表现不同，这取决于它们的 特定组织微环境（TME）。在这里，我们假设肿瘤TME的两面属性 提出TME氧化的特定模式，细胞外pH值（pHe），无机磷酸盐（Pi），氧化还原 和谷胱甘肽（GSH）的稳态作用，利用协调机制，以促进癌细胞的生存 同时对正常细胞具有高毒性和致突变性。该项目的总体目标是 使用于化学TME的体内多功能分析的创新磁共振方法能够改善 早期诊断对恶性转化的预测能力和未来TME靶向治疗的合理设计 抗癌疗法具体目标是：（SA 1）推进磁共振技术， 用于体内实时组织微环境分析的顺磁探针。顺磁探针 利用电子顺磁共振（EPR）和质子-电子双共振（EPR）进行多功能测量。 将推进共振成像（PEDRI）技术，以进行体内实时TME分析。也就是说， 用于同时监测pO 2、pHe和Pi的三苯甲基探针，以及用于pH、GSH和还原的氮氧探针 将优化容量测量。SA 2：进行体内肿瘤微环境分析， 肿瘤进展为恶性。来自（SA 1）的探针阵列将用于进行化学TME 使用我们的PyMT转基因小鼠群体， 自发地发展乳腺癌并模仿人类肿瘤分期。除了L波段EPR之外 光谱测量，PEDRI功能映射将用于评估探针分布， 肿瘤TME的功能异质性。动态对比增强（DCE）MRI将用于量化肿瘤 空间异质性SA 3：确定预后因素并评价组织微环境的有效性 操纵正常化化学TME可能为抗癌TME靶向治疗提供新的基础 干预措施。在SA 3A中，我们将单独执行TME操作，并与标准操作组合使用。 SA 3B的化疗。我们预计，该程序旨在防止/补偿组织缺氧， 酸中毒还将影响组织氧化还原、Pi和GSH，并改善癌前病变小鼠模型的结果。 乳腺病变在目标3B中，我们将测试我们的假设，即TME化学正常化将增加 使用标准化疗，多西他赛的治疗效果，以解决重要的临床 肿瘤解毒和化疗耐药性的问题。