Profiling chemical tumor microenvironment: application for diagnostics & therapy

分析肿瘤化学微环境：诊断应用

基本信息

批准号：
9749962
负责人：
Valery V Khramtsov
金额：
$ 33.28万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
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/9749962
关键词：
Acidosis Address Affect Bicarbonates Biochemical Genetics Breast Cancer Model Cancer Center 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 disorder Future Glutathione Glycolysis Goals Heterogeneity Histologic Homeostasis Human Hypoxia Image Imaging Techniques Knowledge Literature Magnetic Resonance Magnetic Resonance Imaging Malignant - descriptor Malignant Neoplasms Mammary Neoplasms Mammary gland Measurement Measures Metabolism Methodology Methods Monitor Mus Normal Cell Normal tissue morphology Nuclear Magnetic Resonance Oxidation-Reduction Pathologic 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 Use Effectiveness analog angiogenesis anti-cancer anti-cancer therapeutic base breast lesion cancer cell cancer therapy chemotherapy contrast enhanced design docetaxel extracellular imaging approach improved improved outcome in vivo innovation inorganic phosphate malignant breast neoplasm mouse model phenylalanylphenylalanine prevent public health relevance targeted treatment therapeutic effectiveness tumor tumor heterogeneity tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): 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 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 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.

描述（由申请人提供）：如今，由于其特定的组织微环境（TME），恶性细胞经常的行为通常会有所不同。在这里，我们假设肿瘤TME的janus面性特性提出了TME氧合，细胞外pH（PHE），无机磷酸盐（PI），氧化还原和谷胱甘肽（GSH）稳态的特定模式同时对正常细胞剧毒和诱变。该项目的总体目标是启用创新的磁共振方法，用于在体内进行化学TME多功能分析，以提高早期诊断的预测能力，以实现恶性转变和未来的TME-Target抗癌抗癌疗法的理性设计。具体目的是：（SA1）推进体内实时组织微环境分析的磁共振技术和顺磁探针。使用电子顺磁共振（EPR）和质子电子双共振成像（PEDRI）技术进行多功能测量的顺磁探针，将提出用于在体内实时TME分析中执行的。也就是说，将优化用于同时监测PO2，PHE和PI的Trityl探针，以及用于pH，GSH和降低能力测量值的氮氧化物探针。 SA 2：随着肿瘤发展为恶性，进行体内肿瘤微环境分析。（SA1）的探针阵列将用于进行化学TME分析，因为使用我们的PYMT转基因小鼠菌落乳腺肿瘤发展为恶性，从而自发发展乳腺癌并模仿人类肿瘤分期。除L波段EPR光谱测量外，PEDRI功能映射还将用于评估肿瘤TME的探针分布和功能异质性。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操纵的功效。标准化化学TME可能为抗癌TME靶向治疗干预措施提供新的基础。在SA 3A中，我们将仅执行TME操纵，并与SA 3B中的标准化学疗法结合使用。我们预计旨在预防/补偿组织缺氧和酸中毒的程序也会影响组织氧化还原，PI和GSH，并在小鼠癌症前乳腺病变模型中改善预后。在AIM 3B中，我们将检验我们的假设，即TME化学归一化将使用标准化学疗法（多西他赛）提高治疗有效性，以解决肿瘤排毒和耐化学疗法抗性的重要临床问题。