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 #
1R01CA194013-01
Application #
8863918
Study Section
Biomedical Imaging Technology Study Section (BMIT)
Program Officer
Forry, Suzanne L
Project Start
2015-04-01
Project End
2020-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
1
Fiscal Year
2015
Total Cost
$352,275
Indirect Cost
$123,525
Name
Ohio State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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