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.

项目摘要/摘要 如今，人们已广泛认识到，恶性细胞经常以不同的方式行事不同 特定的组织微环境（TME）。在这里，我们假设肿瘤TME的Janus面饰特性 提出TME氧合，细胞外pH（PHE），无机磷酸盐（PI），氧化还原的特定模式 和谷胱甘肽（GSH）稳态来利用精心策划的机制来促进癌细胞的存活 同时对正常细胞剧毒和诱变。该项目的总体目标是 启用用于体内化学TME多功能分析的创新磁共振方法以改进 早期诊断对恶性转变的预测能力和TME靶向的未来合理设计 抗癌治疗学。具体目的是：（SA1）推进磁共振技术和 体内实时组织微环境分析的顺磁性探针。顺磁性探针 使用电子磁共振共振（EPR）和质子电子双 - 的多功能测量 共振成像（PEDRI）技术将采用用于在体内实时TME分析。即， 用于同时监测PO2，PHE和PI的TrityL探针以及pH，GSH和还原的硝酸探针 容量测量将被优化。 SA 2：进行体内肿瘤微环境分析为 肿瘤发展为恶性肿瘤。 （SA1）的探针阵列将用于执行化学TME 随着乳腺肿瘤使用我们的PYMT转基因小鼠的菌落发展为恶性肿瘤的分析 自发发展乳腺癌并模仿人类肿瘤分期。除了L波段EPR 光谱测量，PEDRI功能映射将用于评估探针分布和 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：确定预后因素并评估组织微环境的功效 操纵。标准化化学TME可能为抗癌者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操纵，并与标准结合使用 SA 3B的化学疗法。我们预计这些程序旨在防止/补偿组织缺氧和 酸中毒还会影响组织氧化还原，PI和GSH，并在小鼠前癌模型中改善结果 乳房病变。在AIM 3B中，我们将检验我们的假设，即TME化学标准化将增加 使用标准化学疗法（多西他赛）来解决重要临床的治疗有效性 肿瘤解毒和耐化疗的问题。