The overall goal of this project is to prove the hypothesis that bi-directional interaction between tumor microenvironment and macrophages plays significant role in tumor progression and therapy efficacy. This hypothesis is specifically formulated at the level of living tissue and therefore will be tested in vivo using innovative electron paramagnetic resonance (EPR)-based multifunctional approaches. These approaches will be used to correlate, in vivo, the role of macrophages and macrophage-specific HIF-1a and HIF-2a in the regulation of tumor hypoxia, extracellular pH (pHe), redox and glutathione (GSH); and how deletion of these factors affects clinically-relevant anti-cancer treatment strategies in the PyMT mouse model of breast cancer.
The specific aims are: (SA1) To optimize magnetic resonance modalities for in vivo multifunctional monitoring of tumor tissue parameters: pH, oxygen, redox and GSH. Novel paramagnetic probes and techniques will be optimized for multi-functional application in tumor tissue with the focus on application to the PyMT mammary tumors in mice. (SA2) To investigate the role of macrophages in regulating the tumor microenvironment in breast cancer. We hypothesize that macrophages significantly affect oxygen tension, acidosis, redox and intracellular GSH (EPR signature of tumor microenvironment) in breast cancer, and that despite both being hypoxia-inducible proteins, macrophage HIF-1a and HIF-2a have disparate and opposing roles in the regulation of the these parameters in the tumor microenvironment, and that we can detect changes in corresponding EPR signature between transgenic mice containing the macrophage ablation or HIF-1a or HIF- 2a deletions. (SA3) To investigate macrophage-regulated tumor microenvironment and their role in chemotherapy efficacy in breast cancer. We will test the hypothesis that tumor pO2, pHe, redox and GSH all combine to form a tumor microenvironment profile that can predict levels of success for standard chemotherapies, and macrophages are a lynchpin in tumor microenvironment regulation. Specifically, we will test whether predominance in tumor macrophage polarity (M1/M2) will regulate a tumor microenvironment and the efficacy of standard chemotherapies, such as docetaxel, and whether macrophage HIF-1a deletion will increase docetaxel effectiveness. In summary, the results may provide new insight into the tumor microenvironment and macrophage regulation of efficacy of clinically-relevant anti-cancer therapies.

Public Health Relevance

This project aims to prove the hypothesis that bi-directional interaction between tumor microenvironment and macrophages plays significant role in tumor progression. The experiments using innovative magnetic resonance approaches for multifunctional in vivo tumor tissue monitoring in mice that lack macrophages or hypoxia-regulated macrophage functions in a mouse model of breast cancer may provide new insight into the tumor microenvironment and macrophage regulation of efficacy of clinically-relevant anti-cancer therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA194013-03
Application #
9039554
Study Section
Biomedical Imaging Technology B Study Section (BMIT-B)
Program Officer
Forry, Suzanne L
Project Start
2015-11-05
Project End
2020-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
3
Fiscal Year
2017
Total Cost
$310,606
Indirect Cost
$99,233
Name
West Virginia University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
191510239
City
Morgantown
State
WV
Country
United States
Zip Code
26506
Khramtsov, Valery V (2017) In Vivo Molecular Electron Paramagnetic Resonance-Based Spectroscopy and Imaging of Tumor Microenvironment and Redox Using Functional Paramagnetic Probes. Antioxid Redox Signal :
Poncelet, Martin; Driesschaert, Benoit; Bobko, Andrey A et al. (2017) Triarylmethyl-based biradical as a superoxide probe. Free Radic Res :1-7
Bobko, Andrey A; Evans, Jason; Denko, Nicholas C et al. (2017) Concurrent Longitudinal EPR Monitoring of Tissue Oxygenation, Acidosis, and Reducing Capacity in Mouse Xenograft Tumor Models. Cell Biochem Biophys 75:247-253
Khramtsov, Valery V; Bobko, Andrey A; Tseytlin, Mark et al. (2017) Exchange Phenomena in the Electron Paramagnetic Resonance Spectra of the Nitroxyl and Trityl Radicals: Multifunctional Spectroscopy and Imaging of Local Chemical Microenvironment. Anal Chem 89:4758-4771
Kishimoto, Shun; Krishna, Murali C; Khramtsov, Valery V et al. (2017) In Vivo Application of Proton-Electron Double-Resonance Imaging. Antioxid Redox Signal :
Bobko, Andrey A; Eubank, Timothy D; Driesschaert, Benoit et al. (2017) Interstitial Inorganic Phosphate as a Tumor Microenvironment Marker for Tumor Progression. Sci Rep 7:41233
Driesschaert, Benoit; Bobko, Andrey A; Khramtsov, Valery V et al. (2017) Nitro-Triarylmethyl Radical as Dual Oxygen and Superoxide Probe. Cell Biochem Biophys 75:241-246
Driesschaert, Benoit; Bobko, Andrey A; Eubank, Timothy D et al. (2016) Poly-arginine conjugated triarylmethyl radical as intracellular spin label. Bioorg Med Chem Lett 26:1742-4
Gorodetsky, Artem A; Kirilyuk, Igor A; Khramtsov, Valery V et al. (2016) Functional electron paramagnetic resonance imaging of ischemic rat heart: Monitoring of tissue oxygenation and pH. Magn Reson Med 76:350-8