Profiling chemical tumor microenvironment: Application for diagnostics & therapy

分析肿瘤化学微环境：诊断应用

• 批准号: 10670810
• 负责人: Timothy D Eubank
• 金额: $ 33.73万
• 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 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10670810
• 关键词: Acidity; Animal Cancer Model; Antitumor Drug Screening Assays; Area; Award; Awareness; Biochemical; Biological; Biological Process; Biophysics; Blood; Breast Cancer Model; Characteristics; Chemicals; Clinical; Clinical Trials; Complement; Detection; Development; Diagnostic; Diagnostic Neoplasm Staging; Disease model; Electron Spin Resonance Spectroscopy; Evolution; Female; Food; Free Radicals; Functional Imaging; Funding; Future; Gene Expression; Genetic; Glutathione; Goals; Health; Human; Image; Imaging Techniques; Imaging technology; In Vitro; Knowledge; Learning; Magnetic Resonance; Magnetic Resonance Imaging; Malignant Neoplasms; Mammary Neoplasms; Maps; Measurement; Metabolic; Methodology; Modality; Molecular; Morphology; Mouse Mammary Tumor Virus; Mus; Optical Methods; Oxidation-Reduction; Oxygen; Oxygen saturation measurement; Particulate; Penetration; Phenotype; Phosphorus; Physiologic pulse; Physiological; Process; Progress Reports; Property; Relaxation; Risk; Role; Scanning; Side; Signal Transduction; Site; Spectrum Analysis; Spin Labels; Spin Trapping; Staging; Techniques; Technology; Testing; Therapeutic Intervention; Time; Tissue Sample; Tissue imaging; Tissues; Tumor Tissue; United States National Institutes of Health; biomaterial compatibility; cancer therapy; extracellular; imaging modality; imaging probe; imaging study; improved; in vivo; innovation; inorganic phosphate; insight; interstitial; malignant breast neoplasm; malignant phenotype; molecular imaging; mouse model; polyoma middle tumor antigen; pre-clinical; targeted treatment; therapy resistant; tissue oxygenation; tool; tumor; tumor microenvironment; tumor progression; tumorigenesis

PROJECT SUMMARY/ABSTRACT A key role of the TME in cancer progression, treatment resistance, and as a target for therapeutic intervention is increasingly appreciated. Noninvasive in vivo EPR-based spectroscopy and imaging of tissue oxygenation (pO{2}), extracellular pH (pH{e}), redox, glutathione (GSH) and interstitial inorganic phosphate (Pi) provide unique insights into biological processes in the TME, and may serve as a tool for preclinical screening of anticancer drugs and optimizing TME-targeted therapeutic strategies. In this competitive renewal application, our new directions are built on knowledge and discoveries made during the previous funding period. There are two goals of our R01 renewal proposal. First is to further advance paramagnetic probes and magnetic resonance technology with a focus on improving probes biocompatibility, functionality, and developing multifunctional imaging modalities. Second is to utilize these advances and knowledge accumulated using spectroscopic modalities in the initial R01 project period to obtain further insights into the role of TME in cancer progression, and to test our hypothesis on the roles of interstitial inorganic phosphate in tumorigenesis. The specific aims are: (SA1) To advance molecular multifunctional EPR-based imaging technology and paramagnetic probes. The biocompatible derivatives of multifunctional trityl HOPE probe sensitive to acidity (pH{e}), oxygen (pO{2}) and phosphate (Pi) in Extracellular tissue microenvironment, and dual function nitroxide pH & redox probes will be optimized for concurrent multifunctional imaging using cutting edge imaging modalities, rapid scan EPR imaging and Overhauser-enhanced magnetic resonance imaging. (SA2) To perform molecular imaging of chemical TME as the mammary tumors progress to malignancy. Multifunctional spatially-resolved TME profiling will validate morphological and gene expression-based staging in a mouse model of breast cancer and will map tumor regions with different phenotypes. Tissue samples from the areas with the chemical TME characteristics of a malignant phenotype will be isolated and the TME study will be complemented with immunohistochemical, biochemical, and genetic tissue analysis, and with measurements of total phosphorus and phosphate (Pi) contents in blood. In summary, the developed multifunctional imaging techniques and probes will broaden the scope of preclinical EPR allowing for mapping of physiologically relevant tissue parameters in various disease models in cancers and beyond. New knowledge on stage-specific TME evolution during tumor progression is required to optimize TME-targeted anticancer therapies. It will also provide a scientific basis to evoke public awareness of high content of the phosphate-based modifiers in the processed food and the potential health risk.

项目摘要/摘要 TME在癌症进展，耐药性和作为治疗干预措施的靶标中的关键作用越来越多。组织氧合（PO {2}），细胞外pH（pH {e}），氧化还原，谷胱甘肽（GSH）和间质无机磷酸盐（PI）的无创体内光谱和组织氧合（PO {2}）的成像和成像针对TME的治疗策略。在此竞争性更新应用程序中，我们的新方向建立在上一期资金期间的知识和发现上。我们的R01更新建议有两个目标。首先是进一步推进顺磁探针和磁共振技术，重点是改善探针生物相容性，功能和开发多功能成像方式。其次是利用在初始R01项目期间使用光谱模态积累的这些进步和知识，以进一步了解TME在癌症进展中的作用，并检验我们对肿瘤发生中磷酸间质磷酸的作用的假设。具体目的是：（SA1）推进分子多功能基于EPR的成像技术和顺磁性探针。 The biocompatible derivatives of multifunctional trityl HOPE probe sensitive to acidity (pH{e}), oxygen (pO{2}) and phosphate (Pi) in Extracellular tissue microenvironment, and dual function nitroxide pH & redox probes will be optimized for concurrent multifunctional imaging using cutting edge imaging modalities, rapid scan EPR imaging and大关增强的磁共振成像。 （SA2）随着乳腺肿瘤发展为恶性肿瘤，对化学TME进行分子成像。多功能空间分辨的TME分析将在乳腺癌的小鼠模型中验证基于形态和基因表达的分期，并将绘制具有不同表型的肿瘤区域。将分离具有恶性表型的化学TME特征区域的组织样品，并将TME研究与免疫组织化学，生化和遗传组织分析相辅相成，并测量血液中总磷和磷酸盐（PI）含量。总而言之，开发的多功能成像技术和探针将扩大临床前EPR的范围，以允许在癌症及其他地区的各种疾病模型中绘制生理相关的组织参数。需要在肿瘤进展过程中有关阶段特异性TME演化的新知识，以优化针对TME靶向的抗癌疗法。它还将提供科学依据，以唤起公众对加工食品中磷酸盐基于磷酸盐的改性剂的认识和潜在的健康风险。

项目成果

Electron Paramagnetic Resonance Implemented with Multiple Harmonic Detections Successfully Maps Extracellular pH In Vivo.

• DOI: 10.1021/acs.analchem.2c03194
• 发表时间: 2023-02-28
• 期刊: ANALYTICAL CHEMISTRY
• 影响因子: 7.4
• 作者: Nakaoka, Ririko;Kato, Kazuhiro;Yamamoto, Kumiko;Yasui, Hironobu;Matsumoto, Shingo;Kirilyuk, Igor A.;Khramtsov, Valery V.;Inanami, Osamu;Hirata, Hiroshi
• 通讯作者: Hirata, Hiroshi

The Underexplored Landscape of Hypoxia-Inducible Factor 2 Alpha and Potential Roles in Tumor Macrophages: A Review.

• DOI: 10.3390/oxygen3010005
• 发表时间: 2023-03
• 期刊: Oxygen (Basel, Switzerland)
• 作者: Steinberger KJ;Eubank TD
• 通讯作者: Eubank TD

Microsecond Exchange Processes Studied by Two-Dimensional ESR at 95 GHz.

• DOI: 10.1021/jacs.0c09469
• 发表时间: 2020-12-23
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Dzikovski B;Khramtsov VV;Chandrasekaran S;Dunnam C;Shah M;Freed JH
• 通讯作者: Freed JH

Macrophage and Neutrophil Interactions in the Pancreatic Tumor Microenvironment Drive the Pathogenesis of Pancreatic Cancer.

• DOI: 10.3390/cancers14010194
• 发表时间: 2021-12-31
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Pratt HG;Steinberger KJ;Mihalik NE;Ott S;Whalley T;Szomolay B;Boone BA;Eubank TD
• 通讯作者: Eubank TD

In Vivo EPR Assessment of pH, pO2, Redox Status, and Concentrations of Phosphate and Glutathione in the Tumor Microenvironment.

• DOI: 10.3791/56624
• 发表时间: 2018-03-16
• 期刊: Journal of visualized experiments : JoVE
• 作者: Bobko AA;Eubank TD;Driesschaert B;Khramtsov VV
• 通讯作者: Khramtsov VV