Profiling chemical tumor microenvironment: Application for diagnostics & therapy

分析肿瘤化学微环境：诊断应用

• 批准号: 9981151
• 负责人: Valery V Khramtsov
• 金额: $ 34.42万
• 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/9981151
• 关键词: Acidity; Affect; Animal Cancer Model; Animals; Antineoplastic Agents; Area; Award; Awareness; Biochemical Genetics; Biological; Biological Process; Biophysics; Biopsy Specimen; Blood; Breast Cancer Model; Characteristics; Chemicals; Clinical; Clinical Trials; Complement; Detection; Development; Diagnostic; Diagnostic Neoplasm Staging; Diet; Disease model; Effectiveness; Electron Spin Resonance Spectroscopy; Evolution; Female; Food; Free Radicals; Funding; Future; Gene Expression; Glutathione; Glycolysis; Goals; Health; Human; Image; Imaging Techniques; Imaging technology; In Vitro; Intervention; Knowledge; Knowledge Discovery; Magnetic Resonance; Magnetic Resonance Imaging; Malignant Neoplasms; Mammary Neoplasms; Maps; Measurement; Metabolic; Methodology; Modality; Molecular; Morphology; Mouse Mammary Tumor Virus; Mus; Needle biopsy procedure; Optical Methods; Oxidation-Reduction; Oxygen; Oxygen saturation measurement; Particulate; Penetration; Pharmaceutical Preparations; Pharmacology; 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; base; biomaterial compatibility; cancer therapy; docetaxel; extracellular; image guided; imaging modality; imaging probe; imaging study; improved; improved functioning; in vivo; innovation; inorganic phosphate; insight; interstitial; malignant breast neoplasm; malignant phenotype; molecular imaging; mouse model; pre-clinical; programs; screening; 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.

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.