Profiling chemical tumor microenvironment: application for diagnostics & therapy

项目摘要/摘要 今天，人们越来越广泛地认识到，恶性细胞的行为往往不同，这取决于其 特定组织微环境(TME)。在这里，我们假设肿瘤TME的Janus-Face特性 提出了TME氧化、胞外pH(Phe)、无机磷(PI)、氧化还原的具体模式 和谷胱甘肽(GSH)的稳态作用，利用一种精心安排的机制来促进癌细胞存活 同时对正常细胞具有高度毒性和致突变性。这个项目的总体目标是 使化学物质TME体内多功能分析的创新磁共振方法得到改进 早期诊断对恶性转化和未来TME靶向合理设计的预测力 抗癌疗法。具体目标是：(SA1)推进磁共振技术和 用于活体实时组织微环境分析的顺磁探头。顺磁探头 电子顺磁共振(EPR)和质子-电子双电子共振仪的多功能测量 磁共振成像(Pedri)技术将被先进，以进行活体实时TME分析。也就是说， 用于同时监测PO2、Phe和PI的三叔丁基探针，以及用于pH、GSH和还原的氮氧化物探针 容量测量将得到优化。SA 2：在体内进行肿瘤微环境分析 肿瘤会进展为恶性肿瘤。来自(SA1)的探针阵列将用于执行化学TME 利用我们的pYMT转基因小鼠群体分析乳腺肿瘤进展为恶性的情况 自发地发展成乳腺癌，并模仿人类的肿瘤分期。除了L-乐队EPR 光谱测量，将使用Pedri函数图来评估探针分布和 肿瘤TME的功能异质性。将使用动态对比增强(DCE)MRI对肿瘤进行量化 空间异质性。SA 3：确定预后因素并评估组织微环境的疗效 操纵。化学TME正常化可能为抗癌TME靶向治疗提供新的依据 干预措施。在SA 3A中，我们将单独执行TME操作，并与标准 化疗方案为SA3B。我们预计，旨在预防/补偿组织缺氧和 酸中毒还会影响组织氧化还原、PI和GSH，并改善癌前病变小鼠模型的预后 乳房病变。在目标3B中，我们将测试我们的假设，即TME化学标准化将增强 采用标准化疗方案多西紫杉醇治疗临床疗效重要 肿瘤解毒和化疗耐药问题。

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.