Profiling chemical tumor microenvironment: application for diagnostics & therapy

 描述（由申请人提供）：如今，人们越来越广泛地认识到，恶性细胞通常根据其特定的组织微环境（TME）表现不同。在这里，我们假设肿瘤TME的两面属性，提出TME氧合、细胞外pH值（pHe）、无机磷酸盐（Pi）、氧化还原和谷胱甘肽（GSH）稳态的特定模式可以利用一种协调的机制来促进癌细胞的生存，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创新的磁共振方法能够用于化学TME的体内多功能分析，以提高恶性转化的早期诊断的预测能力，并用于未来TME靶向抗癌疗法的合理设计。具体目标是：（SA 1）推进用于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被改进，以进行体内实时TME分析。即，将优化用于同时监测pO 2、pHe和Pi的三苯甲基探针以及用于pH、GSH和还原能力测量的氮氧探针。SA 2：随着肿瘤进展为恶性肿瘤，进行体内肿瘤微环境分析。来自（SA 1）的探针阵列将用于进行化学TME分析，因为乳腺肿瘤进展为恶性肿瘤，使用我们的PyMT转基因小鼠群体，其自发发展乳腺癌并模拟人类肿瘤分期。除了L-波段EPR光谱测量，PEDRI功能定位将用于评估肿瘤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：确定预后因素并评价组织微环境操作的有效性。使化学TME正常化可能为抗癌TME靶向治疗干预提供新的基础。在SA 3A中，我们将单独进行TME操作，并在SA 3B中结合标准化疗。我们预计，旨在预防/补偿组织缺氧和酸中毒的程序也将影响组织氧化还原、Pi和GSH，并改善癌前乳腺病变小鼠模型的结果。在目标3B中，我们将检验我们的假设，即TME化学正常化将使用标准化疗多西他赛增强治疗效果，以解决肿瘤解毒和化疗耐药性的重要临床问题。

 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.